U.S. patent number 5,830,920 [Application Number 08/639,986] was granted by the patent office on 1998-11-03 for sulfuric acid esters of sugar alcohols.
This patent grant is currently assigned to Hoffmann-La Roche Inc.. Invention is credited to Alexander Chucholowski, Jurgen Fingerle, Niggi Iberg, Hans Peter Marki, Rita Muller, Michael Pech, Marianne Rouge, Gerard Schmid, Thomas Tschopp, Hans Peter Wessel.
United States Patent |
5,830,920 |
Chucholowski , et
al. |
November 3, 1998 |
**Please see images for:
( Certificate of Correction ) ** |
Sulfuric acid esters of sugar alcohols
Abstract
Compounds of the formula ##STR1## wherein n.sup.1 -n.sup.9 are
each independently 0 or 1; m.sup.1 -m.sup.9 are each independently
0 or 1, but with the proviso that at least one of m.sup.1, m.sup.2
and m.sup.3, at least one of m.sup.4, m.sup.5 and m.sup.6 and, when
present, at least one of m.sup.7, m.sup.8 and m.sup.9 is 1; and
wherein X.sup.1 -X.sup.18 each independently is --O--,
--CONR.sup.1,--NR.sup.1 CO-- or --NR.sup.1 --; R.sup.1 is hydrogen
or lower alkyl; W is a benzene or s-triazine; Y.sup.1 -Y.sup.9 each
independently is an aromatic ring systems; A.sup.1 -A.sup.3 each
independently is a residue of a sugar alcohol devoid of the
1-hydroxy group or a derivative thereof, a residue of a sugar acid
devoid of the 1-carboxy group or a derivative thereof or
tris-(hydroxymethyl)-methyl; D is the di-residue of a sugar alcohol
devoid of 2 hydroxy groups or a derivative thereof or the
di-residue of a sugar dicarboxylic acid devoid of 2 carboxy group
or a derivative thereof; Q.sup.1 -Q.sup.3 and Z.sup.1 -Z3 each
independently are the di-residue of a sugar alcohol devoid of 2
hydroxy groups or a derivative thereof or the di-residue of a sugar
dicarboxylic acid devoid of 2 carboxy groups or a derivative
thereof or didesoxyglycopyranoside or a derivative thereof, wherein
at least one hydroxy group of residues A.sup.1 -A.sup.3, D, Q.sup.1
-Q.sup.3 and Z.sup.1 -Z.sup.3 is esterified with sulfuric acid, and
pharmaceutically usable salts thereof are useful for the treatment
of disorders which are characterized by excessive or destructive
proliferation of smooth muscle cells.
Inventors: |
Chucholowski; Alexander
(Grenzach-Wyhlen, DE), Fingerle; Jurgen (Rheinfelden,
DE), Iberg; Niggi (Basel, CH), Marki; Hans
Peter (Basel, CH), Muller; Rita (Basel,
CH), Pech; Michael (Hartheim, DE), Rouge;
Marianne (Basel, CH), Schmid; Gerard (Kienberg,
CH), Tschopp; Thomas (Ettingen, CH),
Wessel; Hans Peter (Heitersheim, DE) |
Assignee: |
Hoffmann-La Roche Inc. (Nutley,
NJ)
|
Family
ID: |
4207454 |
Appl.
No.: |
08/639,986 |
Filed: |
April 26, 1996 |
Foreign Application Priority Data
Current U.S.
Class: |
514/730; 568/809;
568/705; 568/808; 568/715; 536/120; 514/25; 536/4.1; 514/724 |
Current CPC
Class: |
A61P
31/12 (20180101); A61P 43/00 (20180101); C07C
305/10 (20130101); A61P 9/10 (20180101); C07H
15/18 (20130101); C07C 305/06 (20130101); A61P
7/02 (20180101) |
Current International
Class: |
C07C
305/10 (20060101); C07C 305/06 (20060101); C07C
305/00 (20060101); C07H 15/00 (20060101); C07H
15/18 (20060101); A61K 031/045 (); C07C
205/00 () |
Field of
Search: |
;536/4.1,120,22.1
;574/25,738,739 ;514/42,599,730,724,613,616
;568/705,715,809,808 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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|
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|
56575 |
|
Jan 1982 |
|
EP |
|
247721 |
|
Apr 1987 |
|
EP |
|
312086 |
|
Oct 1988 |
|
EP |
|
6603997 |
|
Mar 1966 |
|
NL |
|
Other References
Bioorg. Med. Chem. Lett. 4, pp. 1419-1422 (1994). .
O. Mitsunobu, Synthesis 12, pp. 1-28 (1981). .
R. F. Heck, Organic Reactions 27, pp. 345-390 (1982). .
Teien et al. Thrombosis Research 10, pp. 399-410 (1977). .
Bayer 98(7) (1982):54399d. .
Fisons AG/CA Pharmaceuticals Ltd. 26th Sep. 1966, CA 67:100002d.
.
B. Lamm et al. Acta Chem. Scand. B 41, pp. 202-207 (1987). .
R. A.Murphy et al. J. Med. Chem. 33, pp. 171-178 (1990). .
H. Kapitza & R. Zentel, Makromol Chem. 192, pp. 1859-1872
(1991). .
Y. Le Merrer et al. Heterocycles 25 pp. 541-548 (1987). .
E. Hungerbuhler & D. Seebach, Helvetica Chimica Acta 64 pp.
687-702 (1981). .
E. Weber et al., Chem. Ber. 122 pp. 959-967 (1989). .
Meyer zu Reckendorf, Chem. Ber 107, pp. 869-875 (1974)..
|
Primary Examiner: Peselev; Elli
Attorney, Agent or Firm: Johnston; George W.
Rocha-Tramaloni; Patricia S.
Claims
We claim:
1. A compound of formula ##STR28## wherein n.sup.1 -n.sup.9 are
each independently 0 or 1;
m.sup.1 -m.sup.9 are each independently 0 or 1, but with the
proviso that at least one of m.sup.1, m.sup.2 and m.sup.3, at least
one of m.sup.4, m.sup.5 and m.sup.6 and, at least one of m.sup.7,
m.sup.8 and m.sup.9 is 1; and wherein
X.sup.1 -X.sup.18 each independently is --O--, --CONR.sup.1
--,--NR.sup.1 CO-- or --NR.sup.1 --;
R.sup.1 is hydrogen or lower alkyl;
W is a benzene or s-triazine;
Y.sup.1 -Y.sup.9 each independently is an aromatic ring system;
A.sup.1 -A.sup.3 each independently is a residue of a sugar alcohol
devoid of the 1-hydroxy group or a derivative thereof, a residue of
a sugar acid devoid of the 1-carboxy group or a derivative thereof
or tris-(hydroxymethyl)-methyl;
D is the di-residue of a sugar alcohol devoid of 2 hydroxy groups
or a derivative thereof or the di-residue of a sugar dicarboxylic
acid devoid of 2 carboxy group or a derivative thereof;
Q.sup.1 -Q.sup.3 and Z.sup.1 -Z.sup.3 each independently are the
di-residue of a sugar alcohol devoid of 2 hydroxy groups or a
derivative thereof or the di-residue of a sugar dicarboxylic acid
devoid of 2 carboxy groups or a derivative thereof or
didesoxyglycopyranoside or a derivative thereof, wherein at least
one hydroxy group of residues A.sup.1 -A.sup.3, D, Q.sup.1 -Q.sup.3
and Z.sup.1 -Z.sup.3 is esterified with sulfuric acid with the
proviso that a carbon atom which is not present in a ring system
and which is bonded to hydroxy or hydroxy esterified with sulfuric
acid is not bonded to another hetero atom, or pharmaceutically
acceptable salts thereof.
2. A compound in accordance with claim 1, wherein each of Y.sup.1
-Y.sup.9 are ##STR29## wherein R.sup.2 is hydrogen, halogen, nitro,
lower alkyl, lower alkoxy, lower aralkoxy, carbamoyl or glycerol,
wherein the hydroxy groups present are sulfated or nonsulfated,
G.sup.1 and G.sup.2 are lower alkylene, lower alkenylene, lower
alkynylene or lower alkyleneoxy;
E is a carbon-carbon bond; --O--, --CO, --CH.sub.2 --, --CH.sub.2
--CH.sub.2 --,--CH.dbd.CH--, --C.tbd.C--, --NR.sup.3 --CO-- or
--CO--NR.sup.3 --; and R.sup.3 is hydrogen or lower alkyl.
3. A compound in accordance with claim 1, wherein in formula
Ia,
(A.sup.1 -X.sup.1).sub.m.sup.1 -(Y.sup.1 -X.sup.2
-).sub.n.sup.1-(Q.sup.1 -X.sup.3 -).sub.m.sup.2 -(Y.sup.2
-X.sup.4).sub.n.sup.2 -(-Z.sup.1 -X.sup.5 -).sub.m.sup.3 -(Y.sup.3
-X.sup.6).sub.n.sup.3 is the same as
(A.sup.2 -X.sup.7).sub.m.sup.4 -(Y.sup.4 -X.sup.8 -).sub.n.sup.4
-(Q.sup.2 -X.sup.9 -).sub.m.sup.5 -(Y.sup.5 -X.sup.10).sub.n.sup.5
-(-Z.sup.2 -X.sup.11 -).sub.m.sup.6 -(Y.sup.6
-X.sup.12).sub.n.sup.6 ; and in formula Ib,
(A.sub.1 -X.sup.1).sub.m.sup.1 -(Y.sup.1 -X.sup.2 -).sub.n.sup.1
-(Q.sup.1 -X.sup.3 -).sub.m.sup.2 -(Y.sup.2 -X.sup.4).sub.n.sup.2
-(Z.sup.1 -X.sup.5 -).sub.m.sup.3 -(Y.sup.3 -X.sup.6).sub.n.sup.3
;
(A.sup.2 -X.sup.7).sub.m.sup.4 -(Y.sup.4 -X.sup.8 -).sub.n.sup.4
-(Q.sup.2 -X.sup.9 -).sub.m.sup.5 -(Y.sup.5 -X.sup.10).sub.n.sup.5
-(-Z.sup.2 -X.sup.11 -).sub.m.sup.6 -(Y.sup.6
-X.sup.12).sub.n.sup.6 ; and
(A.sup.3 -X.sup.13).sub.m 7-(Y.sup.7 -X.sup.14 -).sub.n 7-(Q.sup.3
-X.sup.15 -).sub.m 8-(Y.sup.8 -X.sup.16).sub.n 8-(Y.sup.8
-X.sup.16).sub.n 8-(-Z.sup.3 -X.sup.17 -).sub.m 9-(Y.sup.9
-X.sup.18).sub.n.sup.9 are the same.
4. A compound in accordance claim 1, wherein m.sup.2, m.sup.3,
m.sup.5, m.sup.6, m.sup.8, m.sup.9 and n.sup.2, n.sup.3, n.sup.5,
n.sup.6, n.sup.8, n.sup.9 in formula Ib are 0.
5. A compound in accordance with claim 3, wherein m.sup.2, m.sup.3,
m.sup.5, m.sup.6, m.sup.8, m.sup.9 and n.sup.2, n.sup.3, n.sup.5,
n.sup.6, n.sup.8, n.sup.9 in formula Ib are 0.
6. A compound in accordance with claim 1, wherein A.sup.1 -A.sup.3,
D, Q.sup.1 -Q.sup.3, Z.sup.1 -Z.sup.3 are derived from a hexitol, a
pentitol, a tetritol, glycerol or tris-(hydroxymethyl)-methane.
7. A compound in accordance with claim 6, wherein A.sup.1 -A.sup.3,
D, Q.sup.1 -Q.sup.3, Z.sup.1 -Z.sup.3 are glucitol, galactitol,
mannitol, gulitol, arabinitol, ribitol, xylitol, threitol,
erythritol, glycerol, or tris-(hydroxymethyl)methane.
8. A compound in accordance with claim 1, wherein A.sup.1 -A.sup.3
are derived from ribonic acid, gluconic acid or gulonic acid.
9. A compound in accordance with claim 3, wherein A.sup.1 -A.sup.3
are derived from ribonic acid, gluconic acid or gulonic acid.
10. A compound in accordance with claim 1, wherein D, Q.sup.1
-Q.sup.3, Z.sup.1 -Z.sup.3 are derived from tartaric acid,
galactaric acid or glucaric acid.
11. A compound in accordance with claim 1, wherein Q.sup.1
-Q.sup.3, Z.sup.1 -Z.sup.3 are derived from a glycopyranoside.
12. A compound in accordance with claim 1, which is
1,6-Bis-O-[4-[2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-ethyl]-ph
enyl]-2,3,4,5-tetra-O-sulfo-galactitol.
13. A compound in accordance with claim 1, which is
1,6-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-phenyl
]-ethyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol.
14. A compound in accordance with claim 1, which is
1,6-bis-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-2
-yl]-2,3,4,5-tetra-O-sulfo-galactitol.
15. A compound in accordance with claim 1, which is
1,6-bis-O-[6-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-2
-yl]-2,3,4,5-tetra-O-sulfo-galactitol.
16. A compound in accordance with claim 1, which is
1,6-bis-O-[3-biphenyl-4-ylmethoxy-5-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
carbamoyl)-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol.
17. A compound in accordance with claim 1, which is
1,6-bis-O-[6-[(S)-2,3-bis-sulfooxy-propoxy]-3-(2,3,4,5,6-penta-O-sulfo-D-g
lucit-1-ylcarbamoyl)-naphthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol.
18. A compound in accordance with claim 1, which is
1,6-bis-O-[3-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-naphthalen-2-yl]-2
,3,4,5-tetra-O-sulfo-galactitol.
19. A compound in accordance with claim 1, which is
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
yloxy)-benzyl]-phenyl]-D-mannitol.
20. A compound in accordance with claim 1, which is
1,6-didesoxy-2,3,4,5-tetra-O-sulfo-1,6-bis-[3-(2,3,4,5-tetra-O-sulfo-D-ara
binit-1-yloxy)-naphthalen-2-ylcarbonylamino]-galactitol.
21. A compound in accordance with claim 1, which is
1,6-bis-O-[4-[4-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoy
l)-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-
sulfo-galactitol.
22. A compound in accordance with claim 1, which is
1,6-bis-O-[4-[4-O-[4-[(E)-2-[methyl-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
)-carbamoyl]-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,
5-tetra-O-sulfo-galactitol.
23. A compound in accordance with claim 1, which is
1,6-bis-O-[3-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoyl-amino)-3,4-di-O-sulfo-
a-D-glucopyranosid-2-ylcarbamoyl]-naphthalen-1-yl]-2,3,4,5-tetra-O-sulfo-ga
lactitol.
24. A compound in accordance with claim 1, which is
1,6-bis-O-[4-[2-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoylamino)-3,4-di-O-sulfo-a
-D-glucopyranosid-2-ylcarbamoyl]-ethyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galac
titol.
25. A compound in accordance with claim 1, which is
1,6-bis-O-[6-[benzyl
2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamino)-ben
zoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl
]-2,3,4,5-tetra-O-sulfo-galactitol.
26. A compound in accordance with claim 1, which is
1,6-bis-O-[4-[(E)-2-[benzyl
2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamino)-3-nitro-ben
zoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbamoyl]-vinyl]-phenyl]-
2,3,4,5-tetra-O-sulfo-galactitol.
27. A pharmaceutical composition comprising an effective amount of
a compound of the formula ##STR30## wherein n.sup.1 -n.sup.9 are
each independently 0 or 1;
m.sup.1 -m.sup.9 are each independently 0 or 1, but with the
proviso that at least one of m.sup.1, m.sup.2 and m.sup.3, at least
one of m.sup.4, m.sup.5 and m.sup.6 and, at least one of m.sup.7,
m.sup.8 and m.sup.9 is 1; and wherein
X.sup.1 -X.sup.18 each independently is --O--, --CONR.sup.1
--,--NR.sup.1 CO-- or --NR.sup.1 --;
R.sup.1 is hydrogen or lower alkyl;
W is benzene or s-triazine;
Y.sup.1 -Y.sup.9 each independently is an aromatic ring system;
A.sup.1 -A.sup.3 each independently is a residue of a sugar alcohol
devoid of the 1-hydroxy group or a derivative thereof, a residue of
a sugar acid devoid of the 1-carboxy group or a derivative thereof
or tris-(hydroxymethyl)-methyl;
D is the di-residue of a sugar alcohol devoid of 2 hydroxy groups
or a derivative thereof or the di-residue of a sugar dicarboxylic
acid devoid of 2 carboxy group or a derivative thereof;
Q.sup.1 -Q.sup.3 and Z.sup.1 -Z.sup.3 each independently is the
di-residue of a sugar alcohol devoid of 2 hydroxy groups or a
derivative thereof or the di-residue of a sugar dicarboxylic acid
devoid of 2 carboxy groups or a derivative thereof or
didesoxyglycopyranoside or a derivative thereof, wherein at least
one hydroxy group of residues A.sup.1 -A.sup.3, D, Q.sup.1 -Q.sup.3
and Z.sup.1 -Z.sup.3 is esterified with sulfuric acid with the
proviso that a carbon atom which is not present in a ring system
and which is bonded to hydroxy or hydroxy esterified with sulfuric
acid is not bonded to another hetero atom, and pharmaceutically
acceptable salts thereof and an inert carrier.
Description
SUMMARY OF THE INVENTION
The present invention relates to esters of sugar alcohols and sugar
alcohol-like compounds of formulas ##STR2## wherein n.sup.1
-n.sup.9 are each independently 0 or 1;
m.sup.1 -m.sup.9 are each independently 0 or 1, but with the
proviso that at least one of m.sup.1, m.sup.2 and m.sup.3, at least
one of m.sup.4, m.sup.5 and m.sup.6 and, when present, at least one
of m.sup.7, m.sup.8 and m.sup.9 is 1; and wherein
X.sup.1 -X.sup.18 each independently are --O--, --CONR.sup.1 --,
--NR.sup.1 CO-- or --NR.sup.1 --;
R.sup.1 is hydrogen or lower alkyl;
W is a benzene group or a s-triazine group;
Y.sup.1 -Y.sup.9 each independently are aromatic ring systems;
A.sup.1 -A.sup.3 each independently are a residue of a sugar
alcohol devoid of the 1-hydroxy group or a derivative thereof, a
residue of a sugar acid devoid of the 1-carboxy group or a
derivative thereof or the tris-(hydroxymethyl)-methyl group;
D is the di-residue of a sugar alcohol devoid of 2 hydroxy groups
or a derivative thereof or the di-residue of a sugar dicarboxylic
acid devoid of 2 carboxy group or a derivative thereof;
Q.sup.1 -Q.sup.3 and Z.sup.1 -Z.sup.3 each independently are the
di-residue of a sugar alcohol devoid of 2 hydroxy groups or a
derivative thereof or the di-residue of a sugar dicarboxylic acid
devoid of 2 carboxy groups or a derivative thereof or a
didesoxyglycopyranoside residue or a derivative thereof, with at
least one hydroxy group of residues A.sup.1 -A.sup.14, D, Q.sup.1
-Q.sup.3 and Z.sup.1 -Z.sup.3 being esterified with sulfuric acid,
and pharmaceutically usable salts thereof.
A carbon atom which is not present in a ring system and which
carries a free hydroxy group or a hydroxy group esterified with
sulfuric acid should not be simultaneously bonded to a further
hetero atom.
In another aspect, the invention relates to pharmaceutical
preparations containing a compound of formula Ia or Ib or a salt
thereof; the use of the compounds of formula Ia or Ib and their
salts as medicaments, especially for the treatment and/or
prophylaxis of disorders which are characterized by excessive or
destructive proliferation of smooth muscle cells and of
artereosclerotic vascular wall changes, for example, for preventing
restenosis after coronary or peripheral angioplasty or after bypass
operations, and, respectively, for the production of medicaments
for the said indications; as well as a process for the manufacture
of the compounds of formula Ia or Ib and their salts.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a bar graph of the cross sectional area of the neointima
in rat carotids of animals administered a compound of the invention
compared to animals administered heparin and placebo.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the formula ##STR3##
wherein n.sup.1 -n.sup.9 are each independently 0 or 1;
m.sup.1 -m.sup.9 are each independently 0 or 1, but with the
proviso that at least one of m.sup.1, m.sup.2 and m.sup.3, at least
one of m.sup.4, m.sup.5 and m.sup.6 and, when present, at least one
of m.sup.7, m.sup.8 and m.sup.9 is 1; and wherein
X.sup.1 -X.sup.18 each independently is --O--, --CONR.sup.1 --,
--NR.sup.1 CO-- or --NR.sup.1 --;
R.sup.1 is hydrogen or lower alkyl;
W is a benzene or s-triazine;
Y.sup.1 -Y.sup.9 each independently is an aromatic ring system;
A.sup.1 -A.sup.3 each independently is a residue of a sugar alcohol
devoid of the 1-hydroxy group or a derivative thereof, a residue of
a sugar acid devoid of the 1-carboxy group or a derivative thereof
or tris-(hydroxymethyl)-methyl;
D is the di-residue of a sugar alcohol devoid of 2 hydroxy groups
or a derivative thereof or the di-residue of a sugar dicarboxylic
acid devoid of 2 carboxy group or a derivative thereof;
Q.sup.1 -Q.sup.3 and Z.sup.1 -Z.sup.3 each independently is the
di-residue of a sugar alcohol devoid of 2 hydroxy groups or a
derivative thereof or the di-residue of a sugar dicarboxylic acid
devoid of 2 carboxy groups or a derivative thereof or
didesoxyglycopyranoside or a derivative thereof, wherein at least
one hydroxy group of residues A.sup.1 -A.sup.3, D, Q.sup.1 -Q.sup.3
and Z.sup.1 -Z.sup.3 are esterified with sulfuric acid with the
proviso that a carbon atom which is not present in an aromatic ring
system and which is bonded to hydroxy or hydroxy esterified with
sulfuric acid is not bonded to another hetero atom, and
pharmaceutically usable salts thereof.
The following structural elements are features of compounds of
formulas Ia and Ib:
a) Mono-residues of sugar alcohols or sugar acids which are linked
via a suitable functional group, for example, A.sup.1 --X.sup.1,
A.sup.2 --X.sup.7 and the like.
b) di-residues of sugar alcohols or sugar acids or of
didesoxyglycopyranosides which are linked via two suitable
functional groups, for example, X.sup.6 --D--X.sup.12, X.sup.2
--Q.sup.1 --X.sup.3, X.sup.4 --Z.sup.1 --X.sup.5 and the like.
c) aromatic units which are linked via two suitable functional
groups, for example, X.sup.1 --Y.sup.1 --X.sup.2, X.sup.3 --Y.sup.2
--X.sup.4 and the like.
d) aromatic units which are linked via three suitable functional
groups, for example, ##STR4##
Compounds of different molecular size can be synthesized by linking
these structural elements.
Compounds of the invention contain at least three groups which are
derived from a sugar alcohol, a sugar acid or from a
glyco-pyranoside.
In a preferred embodiment of a compound of formula Ia or Ib the two
or, respectively, three side chains are identical; each of Y.sup.1
-Y.sup.9 are ##STR5## wherein R.sup.2 is hydrogen, halogen, nitro,
lower alkyl, lower alkoxy, lower aralkoxy, carbamoyl or glycerol,
wherein the hydroxy groups present are optionally sulfated,
G.sup.1 and G.sup.2 are lower alkylene, lower alkenylene, lower
alkynylene or lower alkyleneoxy;
E is a carbon-carbon bond; --O--, --CO, --CH.sub.2 --, --CH.sub.2
--CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, NR.sup.3 --CO-- or
--CO--NR.sup.3 --; and R.sup.3 is hydrogen or lower alkyl; and
A.sup.1 -A.sup.3, D, Q.sup.1 -Q.sup.3, Z.sup.1 -Z.sup.3 are derived
from a hexitol, a pentitol, a tetritol, glycerol or
tris-(hydroxymethyl)-methane.
In the aromatic units which are linked via three suitable
functional groups there are preferred compounds of formula Ib in
which m.sup.2, m.sup.3, m.sup.5, m.sup.6, m.sup.8, m.sup.9 and
n.sup.2, n.sup.3, n.sup.5, n.sup.6, n.sup.8 and n.sup.9 are O.
Any conventional sugar alcohol can be used. Examples of suitable
sugar alcohols from which the residues A.sup.1 -A.sup.3, D, Q.sup.1
-Q.sup.3 and Z.sup.1 -Z.sup.3 are derived are hexitols such as
glucitol, galactitol, mannitol and gulitol; pentitols such as
arabinitol, ribitol and xylitol; tetritols such as threitol and
erythritol or glycerol. Derivatives of such sugar alcohols can be
mono- or multiply-desoxygenated sugar alcohols such as
L-rhamnitol.
Ribonic acid, gluconic acid and gulonic acid are examples of sugar
carboxylic acids from which residues A.sup.1 -A.sup.3 are
derived.
Tartaric acid, galactaric acid and glucaric acid are examples of
sugar dicarboxylic acids from which residues D, Q.sup.1 -Q.sup.3
and Z.sup.1 -Z.sup.3 are derived
These sugar alcohols and sugar carboxylic acids can be present in
the D- or L-form or as racemates, with the naturally occurring form
or the form which corresponds to the basic, naturally occurring
sugar being preferred.
Preferably, residues A.sup.1 -A.sup.3 are derived from glucitol,
arabinitol, glycerol or from tris-(hydroxymethyl)-methane.
A derivative of a sugar alcohol is, for example, a corresponding
ether at C.sub.1 or a cyclic compound of the formula ##STR6##
A derivative of a didesoxyglycopyranoside residue is, for example,
a corresponding ether at C.sub.1.
Examples of aromatic ring systems Y.sup.1 -Y.sup.9 in formula Ia or
Ib are residues of formulas a)-h): ##STR7## wherein R.sup.2 is
hydrogen, halogen, nitro, lower alkyl, lower alkoxy, lower
aralkoxy, carbamoyl or glycerol, with hydroxy groups present also
being optionally sulfated,
G.sup.1 and G.sup.2 are lower alkylene, lower alkenylene, lower
alkynylene or lower alkyleneoxy;
E is a carbon-carbon bond; --O--, --CO, --CH.sub.2 --, --CH.sub.2
--CH.sub.2 --,--CH.dbd.CH--, --C.tbd.C--, --NR.sup.3 --CO-- or
--CO--NR.sup.3 --; and R.sup.3 is hydrogen or lower alkyl.
The term "lower alkyl" and "lower alkylene" means straight-chain or
branched saturated hydrocarbon groups with up to 7, preferably up
to 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, tert.butyl and the like.
In an analogous manner, the terms "lower alkenyl" and "lower
alkenylene" as well as "lower alkynyl" and "lower alkynylene" mean
unsaturated hydrocarbon groups which contain a double or,
respectively, triple bond and which have up to 7, preferably up to
4, carbon atoms such as vinyl, allyl, ethynyl, propargyl and the
like.
The term "lower alkoxy" and "lower alkyleneoxy" mean alkyloxy
groups and, respectively, alkyleneoxy groups in the sense of the
above description of the terms "lower alkyl" and, respectively,
"lower alkylene".
The term "aralkoxy" means alkoxy groups substituted by phenyl and
biphenyl groups.
The term "halogen" means fluorine, chlorine, bromine and iodine, of
which bromine is preferred.
Phenylene groups of formulae a)-c) are preferably 1,4-phenylene
groups.
In formulae f) and g) the bonds emanating from the rings are
preferably situated in the p-position to one another.
Examples of salts of compounds of formulas Ia or Ib are alkali
metal salts such as Na or K salts, ammonium salts and salts of
tertiary amines such as triethylamine or pyridinium or imidazolium
salts or quaternary ammonium salts such as
dodecyl-trimethyl-ammonium, ethylpyridinium and benzethonium salts;
as well as alkaline earth metal salts such as Ca or Mg salts.
Preferred compounds of formula I are:
1,6-Bis-O-[6-methoxy-3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-nap
hthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt
(Example 20); ##STR8##
1,6-Bis-O-[8-methoxy-3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-na
p hthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt (Example 21); ##STR9##
1,6-Bis-O-[4-[4-O-[3-(2,3,4,5,6penta-O-sulfo-D-glucit-1-ylcarbamoyl)-napht
h
alen-2-yl]-2,3,-di-O-sulfo-L-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-sulfo-
galactitol octadecasodium salt (Example 50); ##STR10##
1,6-Bis-O-[3-[4-O-[3-(2,3,4,5,6penta-O-sulfo-D-glucit
1-ylcarbamoyl)-naphthalene-2-yl]-2,3-di-0-sulfo-L-threit-1-yloxy]-naphthal
en-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol octadecasodium salt
(Example 54); ##STR11##
1,6Bis-O-[4-[(E)-2-[benzyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluco
n
oylamino)-3,4-di-O-sulfo-a-D-glucopyranosid-2-ylcarbamoyl]-vinyl]-phenyl]-2
,3,4,5-tetra-O-sulfo-galactitol octadecasodium salt (Example 57);
##STR12##
Especially preferred compounds of general formula I are:
1,6-Bis-O-[4-[2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-ethyl]-phe
nyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt (Example
6), ##STR13##
1,6-Bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1ylcarbamoyl)-phenyl]
- ethyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt (Example 11), ##STR14##
1,6-Bis-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-2
- yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt
(Example 14), ##STR15##
1,6-Bis-O-[6-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-2
- yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt
(Example 16), ##STR16##
1,6Bis-O-[3-biphenyl-4-ylmethoxy-5-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylc
a rbamoyl)-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt (Example 17), ##STR17##
1,6-Bis-O-[6-[(S)-2,3-bis-sulfoxy-propoxy]-3-(2,3,4,5,6-penta-O-sulfo-D-gl
u
cit-1-ylcarbamoyl)-naphthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol
octadecasodium salt (Example 22), ##STR18##
1,6-Bis-O-[3-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-naphthalen-2-yl]-2
, 3,4,5-tetra-O-sulfo-galactitol dodecasodium salt (Example 40),
##STR19##
2,3,4,5-Tetra-O-sulfo-1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
y loxy)-benzyl]-phenyl]-D-mannitol dodecasodium salt (Example 43),
##STR20##
1,6-Didesoxy-2,3,4,5-tetra-O-sulfo-1,6-bis-[3-(2,3,4,5-tetra-O-sulfo-D-ara
b init-1-yloxy)-naphthalen-2-ylcarbonylamino]-galactitol
dodecasodium salt (Example 45), ##STR21##
1,6Bis-O-[4-[4-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl
)
-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-su
lfo-galactitol octadecasodium salt (Example 48), ##STR22##
1,6Bis-O-[4-[4-O-[4-[(E)-2-[methyl-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)
-
carbamoyl]-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-
tetra-O-sulfo-galactitol octadecasodium salt (Example 52),
##STR23##
1,6Bis-O-[3-[benzyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoylami
n
o)-3,4-di-O-sulfo-a-D-glucopyranosid-2-ylcarbamoyl]-naphthalen-1-yl]-2,3,4,
5-tetra-O-sulfo-galactitol octadecasodium salt (Example 56),
##STR24##
1,6-Bis-O-[4-[2-[benzyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoy
l
amino)-3,4-di-O-sulfo-a-D-glucopyranosid-2-ylcarbamoyl]-ethyl]-phenyl]-2,3,
4,5-tetra-O-sulfo-galactitol octadecasodium salt (Example 58),
##STR25##
1,6-Bis-O-[6-[benzyl-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-sulfo-D-
g
lucit-1-ylamino)-benzoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbam
oyl]-naphthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol
octadecasodium salt (Example 59), ##STR26##
1,6-Bis-O-[4-[(E)-2-[benzyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-sulfo-D-g
l
ucit-1-ylamino)-3-nitro-benzoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-y
lcarbamoyl]-vinyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol
octadecasodium salt (Example 61), ##STR27##
The compounds defined hereinbefore can be prepared by reacting a
corresponding, non-sulfated compound with a sulfating agent.
The sulfation in accordance with the invention can be performed
using methods which are known per se for the sulfation of hydroxy
groups. Examples of sulfating agents are SO.sub.3 complexes such as
SO.sub.3.pyridine, SO.sub.3.trimethylamine, SO.sub.3.dioxan and
SO.sub.3.dimethylformamide. Further examples of sulfating agents
are chlorosulfonic acid, mixtures of chlorosulfonic acid and
sulfuric acid, and piperidine N-sulfate.
The reaction is conveniently effected in a suitable solvent,
especially a polar solvent, for example, dimethylformamide,
dimethyl sulfoxide or hexamethylphosphortriamide. The reaction can
be carried out at room temperature or at an elevated temperature,
for example, at 20.degree.-70.degree. C., whereby the degree of
sulfation can be influenced by varying the reaction duration and
temperature. The degree of sulfation achieved in each case can be
determined by HPLC. In a preferred embodiment, all or practically
all free hydroxy groups are sulfated by suitable choice of reaction
duration and temperature. The working up of the reaction mixture
and, respectively, the isolation of the reaction product can be
effected according to known methods, for example, by gel filtration
or ultrafiltration. Conveniently, the reaction mixture is treated,
prior to the working up, with a compound which is sufficiently
basic to be capable of forming a salt with the sulfonic acid groups
in the compounds defined hereinbefore, for example, with an alkali
metal acetate such as sodium acetate, and the compound of formula
Ia or Ib is isolated in salt form, for example, as the sodium
salt.
The starting materials for the process in accordance with the
invention, that is, the non-sulfated compounds corresponding to the
compounds of formulas Ia and Ib, can be prepared as described in
the Examples hereinafter or in analogy thereto. The various
intermediates via which substances of formulas Ia and Ib are
prepared can in general be prepared stepwise as follows beginning
with known compounds or compounds which are readily accessible in
analogy to known compounds:
Residues of sugar alcohols, didesoxyglycopyranosides or the
tris-(hydroxymethyl)-methyl residue as well as derivatives of sugar
mono- and di-carboxylic acids, hydroxy functions of which are free
or are protected by usual protecting groups such as acetonides,
methylene acetals, aryl methyl ethers, alkyl or aryl esters, and
the like, having desoxy sites can be closed to oxirane rings or
with carboxylic acid functions to 5- or 6-membered lactones, and
which carry one or, respectively, two functional groups suitable
for the subsequent reaction can be linked according to different
linkage patterns and in variable sequence by the simultaneous
formation of one or more new bonds per reaction step with likewise
suitably functionalized aromatic units Y.sup.1 -Y.sup.9 or to the
aromatics W or in their absence with other suitable mono- or
difunctional polyol derivatives. Before the linkage reaction is
repeated, the functional groups required for the linkage reaction
must in each case be prepared for the next linkage reaction by
removing a protecting group, including also the reduction of a
nitro group, or by introducing a suitable activating function
unless bifunctional compounds are reacted selectively at only one
functional site. When repeating the linkage reaction, at least one
of the units to be linked is already a more complex compound, which
not only has polyol derivatives but also aromatic sub-units;
optionally now the fresh linkage reaction can also be carried out
between two aromatic sub-units. The non-sulfated precursors to
formulas Ia and Ib are obtained after the structure has been
synthesized and after the protecting groups have been removed.
When the linkage reaction comprises the formation of an amide bond,
then this can be formed by reacting a component having a free amino
function with the second component in the form of an aliphatic
ester, lactone, an acid chloride or an acid function activated
according to known methods in peptide chemistry (mixed anhydride or
active ester).
When the linkage reaction is the formation of an ether function,
then free hydroxy functions can be linked to a sugar residue with a
phenol or a benzylic or allylic alcohol according to known methods
either without previous activation of the alcohol function
according to Mitsunobu (O. Mitsunobu, Synthesis 12, 1 (1981)) or
after activation of the alcohol function. Such an activation can be
effected by conversion into halides or alkylsulfonates or
arylsulfonates or by formation of an epoxide with an adjacent
hydroxy function.
When the linkage reaction is the formation of an arylamine, then
this can be achieved by known methods for reacting aminoglycitols
with activated aromatics.
The synthesis of aromatic residues with synthones which already
contain polyol derivatives--optionally protected at the hydroxy
functions--can be carried out using C--C bond-forming reactions.
Thereby, there are preferably used reactions which can proceed
under mild reaction conditions, such as by palladium-catalyzed
vinylation and acetylynation reactions of the "Heck" type (R. F.
Heck, Organic Reactions 27, 345 (1982)).
The removal of any protecting groups still present after synthesis
of the structure is effected according to generally conventional
methodology.
Solid carrier reaction technology is especially suitable for the
synthesis of asymmetric compounds. Thereby, a first synthesis unit
is bonded to a suitably functionalized resin via a labile function,
for example, a labile amide function. After subsequent liberation
of a suitable functional group by removing a protecting group which
may be present, a monoreaction can now be achieved selectively not
only with a mono- but also with a difunctional synthone in excess.
Thereby, a functional group remains in the compound bonded to the
resin and a further reaction with a second bifunctional unit can
follow directly. This procedure can be repeated several times. A
monofunctional polyol derivative can finally be used to break the
chain. A possible linkage reaction, to which this principle can be
applied, is the formation of ether functions. Thereby, the
aforementioned reaction conditions for the formation of ether bonds
are used. The compound bonded to the resin can finally be cleaved
off from the resin by a specific cleavage reaction, for example,
under acidic conditions; then after removing any protecting groups
still present at non-sulfated precursor of the compounds defined
hereinbefore is obtained.
The compounds in accordance with the invention inhibit the
migration and proliferation of smooth muscle cells of the vascular
wall. They thus are useful for the treatment and/or prophylaxis of
disorders which are characterized by excessive or destructive
proliferation of smooth muscle cells and of arteriosclerotic
changes of the vascular wall, especially for the prevention of
restenosis after coronary or peripheral angioplasty or after bypass
operations. In principle, these substances can be used for the
treatment and/or prophylaxis of all conditions in which migration
or proliferation of smooth muscle cells plays a role.
In contrast to heparin, these compounds have no AT.sub.III activity
(antithrombin III) and therefore no inhibiting effect on
coagulation factors IIa and Xa. Accordingly, their blood
coagulation-inhibiting activity is very much lower than that of
heparin and thus the risk of bleeding in the case of therapy with
these substances is minimal.
Since heparin-binding proteins play an important role in various
illnesses, heparin-like substances such as the compounds in
accordance with the invention can, in addition, also be used for
the treatment of these illnesses: for example, infection by various
viruses (herpes, HIV) is inhibited by such substances, arterial
thrombosis (vWF, platelet adhesion) is inhibited by such
substances, activation of the complementary system (for example, in
the case of reperfusion) can be diminished and various growth
factors or cytokines (for example, bFGF in tumors) can be
inhibited.
The pharmacological activities of the compounds in accordance with
the invention can be demonstrated in the test procedures described
hereinafter:
Antiproliferative activity
The antiproliferative activity of a substance is expressed as the
r.sub.i value which is a comparative value to the corresponding
activity of heparin and which was determined in cell cultures as
follows: rat smooth muscle cells were applied to cell culture
plates in a density of 8.times.10.sup.3 cells/well, medium: DMEM
(Dulbecco Modified Eagle Medium) with 10% FCS (fetal calf serum);
cultivation at 37.degree. C. and 5% CO.sub.2. After 4 hours, the
number of adhered cells was determined and the substances to be
tested (100 .mu.g/ml, dissolved in H.sub.2 O) were added. The
controls were a) cells to which test compound was not added and b)
cells which had been treated with heparin (100 .mu.g/ml).
Subsequently, the cells were incubated for 48 h. and thereafter the
cell count was determined once more.
The inhibition i of the cell growth, that is, the reduction in the
growth rate of the cells in per cent compared to the control, was
calculated from these values. ##EQU1## with the growth rate .mu.
being calculated as ##EQU2## in which Z is the number of cells and
d is the time in days.
Finally, r.sub.i --the relative inhibitory activity--which
expresses the activity of a substance (at 100 .mu.g/ml) in
comparison to the activity of heparin in the same concentration in
the same experiment, was calculated ##EQU3## Blood coagulation
inhibition
The blood coagulation-inhibiting activity was determined as
follows:
Inhibition of thrombin or factor Xa in the chromogenic substrate
assay (Teien et al., Thrombosis Research 10, 399-410 (1977)): The
determination was effected in a Cobas-Bio centrifugal automatic
spectrophotometer. The buffer solution used consisted of 50 mM Tris
buffer, 180 mM NaCl, 7.5 mM EDTA Na.sub.2, 1% PEG 6000 and 0.02%
Tween 80, pH 8.4. The assay solution consisted of 50 .mu.l of
buffer, 30 .mu.l of antithombin III (1 U/ml, Kabi Diagnostica) and
20 .mu.l of plasma which contained various concentrations of test
compounds. 30 .mu.l of sample solution and 20 .mu.l of water with
180 .mu.l of thrombin (1 U/ml, thrombin reagent, Roche Basle) were
added to the test cuvette in the automatic analyzer. After
incubation at 37.degree. C. for 240 seconds, 60 .mu.l of S-2238
(H-D-Phe-Pip-Arg-NH.pNA, Kabi Diagnostica, Mondal, Sweden, 0.75 mM
in water) and 20 .mu.l of water were added. The liberation of pNA
(p-nitro-aniline) was followed during 60 seconds at 405 nM in 10
second intervals in comparison to water as the blank. The
inhibitory activity is given as the IC.sub.50, which is the
concentration [.mu.g/ml] at which the amidolytic activity of
thrombin is reduced by 50% in comparison to the plasma control
value.
The inhibition of factor Xa was measured in the same manner using a
solution of factor Xa (2.8 nkat/ml and 2 mM S-2222
(Bz-CO-Ile-Glu-Arg-NH.pNA, Kabi Diagnostica) in water in place of
thrombin and, respectively, S-2238.
The activity data obtained in the previously described test
procedures with a representative number of compounds of formula I
are given in the following Table:
______________________________________ Antiproliferative
Anticoagulavite Activity Activity IC.sub.50 [.mu.g/ml] Example
r.sub.i Thrombin Factor Xa ______________________________________ 6
0.7 >1000 >1000 11 2.2 >1000 >1000 14 1.5 >1000
>1000 16 2.1 >1000 >1000 17 1.5 >1000 >1000 22 2.1
>1000 >1000 40 1.4 >1000 >1000 43 1.3 >1000 >1000
45 1.4 >1000 >1000 48 2.7 >1000 >1000 52 0.8 >1000
>1000 56 1.7 >1000 >1000 58 1.8 >1000 >1000 59 1.8
>1000 >1000 61 2.4 >1000 >1000 Heparin 1.0 1.9 2.7
______________________________________
In vivo assay for determining the antiproliferative activity of the
compounds in accordance with the invention in damaged rat
carotids.
The left carotids of male Wistar Kyoto rats (300-400 g) were, after
narcosis, damaged with a 2F embolectomy catheter by pulling the
catheter in the pumped-up state through the vessel three times.
After wound management, the animals were kept in pairs with
standard feed and water ad libidum.
The compounds were administered in concentrations of 0.3-1 mg/kg/h
i.v. For this purpose, an osmotic minipump was implanted under the
dorsal skin of the animals during the narcosis and was connected
with the jugular vein. Thus, the compounds could be administered
constantly during the entire test period of 14 days.
After 14 days, proliferative tissue (neointima) had formed, the
size of which could be determined morphometrically on histological
cross-sections. In order to do this, the rats were sacrificed and
perfusion-fixed with glutaraldehyde.
The cross sectional area of the neointima in rat carotids 14 days
after balloonisation was significantly reduced (p<0.01, t-test)
after i.v. administration of the compound of Example 6 (0.3
mg/kg/h). Thus, Example 6 achieved a comparable effect to that of
concentrated heparin (the number of animals n is given in the FIG.
1; average.+-.SEM).
The test results show that the compounds in accordance with the
invention possess an antiproliferative activity which corresponds
to (or approximates) or is greater than that of heparin, but in
contrast to heparin they show no or only a much lower
anti-coagulation activity.
The medicaments based on the compounds in accordance with the
invention can be administered enterally, for example, orally in the
form of tablets, coated tablets, dragees, hard and soft gelatin
capsules, solutions, emulsions or suspensions, or rectally, for
example, in the form of suppositories. The administration is,
however, preferably effected parenterally, for example, in the form
of injection solutions.
The active substance can be mixed with pharmaceutically inert,
inorganic or organic excipients for the production of tablets,
coated tablets, dragees and hard gelatine capsules. Lactose, corn
starch or derivatives thereof, talc, stearic acid or its salts can
be used for example, as such excipients for tablets, dragees and
hard gelatin capsules. Suitable excipients for soft gelatin
capsules are, for example, vegetable oils, waxes, fats, semi-solid
and liquid polyols; depending on the nature of the active
ingredient no excipients are, however, usually required in the case
of soft gelatin capsules. Suitable excipients for the production of
solutions and syrups are, for example, water, polyols, sucrose,
invert sugar and glucose, suitable excipients for injection
solutions are, for example, water, alcohols, polyols, glycerol and
vegetable oils. Suitable excipients for suppositories are for
example, natural or hardened oils, waxes, fats and semi-liquid or
liquid polyols.
The pharmaceutical preparations can also contain preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, flavorants, salts for varying the osmotic pressure,
buffers, coating agents or antioxidants. In the case of enteral
administration the resorption of the active ingredient can be
enhanced with the aid of liposomes.
The dosage of the active ingredient can vary within wide limits and
will, of course, be fitted to the individual requirements in each
particular case. In general, in the case of parenteral
administration a dosage of about 0.1 to 100 mg/kg, preferably of
about 1.5 to 15 mg/kg, per day should be appropriate for adults,
although the upper limit just given can also be exceeded when this
is found to be indicated.
The invention is illustrated by the following Examples.
EXAMPLE 1
A. 1.024 g of
4,4'-dioxo-5,5'-(2-hydroxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-car
boxylic acid disodium salt) (Neth. Appl. NL 6,603,997, Preparation
of dichromonyl derivatives, Fisons Pharmaceuticals Ltd., 26th Sep.
1966, CA 67:100002d) were suspended in 15 ml of acetonitrile and 5
ml of dimethylformamide, subsequently treated with 0.5 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.704 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.73 g of D-glucamine followed by 10 ml of
dimethylformamide were added and the mixture was stirred at room
temperature for a further 18 hours. Thereupon, the reaction mixture
was diluted several times with water and evaporated several times
at 40.degree.-50.degree. C. under reduced pressure, and the residue
was treated with 20 ml of pyridine and 20 ml of acetic anhydride
and stirred at room temperature for a further 60 hours. Then, this
reaction mixture was again concentrated, the residue was treated
with ice-water and 1N hydrochloric acid and extracted with
methylene chloride. The combined methylene chloride phases were
dried over magnesium sulfate and concentrated, and the residue was
chromatographed on silica gel with ethyl acetate. The product
fraction thereby obtained was dissolved in 11 ml of methanol and 3
ml of tetrahydrofuran and treated with 0.75 ml of 1 molar sodium
methylate solution in methanol. The reaction mixture was stirred at
room temperature for 2 hours.
5-[2-Hydroxy-3-[2-(D-glucit-1-ylcarbamoyl)-4-oxo-4H-1-benzopyran-5-yloxy]-
propoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid D-glucit-1-ylamide
was obtained as a colorless powder, MS: m/z 795.4
([M+H].sup.+).
B. A suspension of 3.2 g of
5-[2-hydroxy-3-[2-(D-glucit-1-ylcarbamoyl)-4-oxo-4H-1-benzopyran-5-yloxy]-
propoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid D-glucit-1-ylamide
and 12.0 g of sulfur trioxide trimethylamine complex in 40 ml of
absolute dimethylformamide was stirred at 70.degree. C. for 18
hours. After cooling, the mixture was treated with 10 g of sodium
acetate and 50 ml of water and evaporated, and the residue was
treated several times with water and again evaporated. The
thus-obtained residue was suspended in 300 ml of absolute methanol
and mixed intensively. The insoluble residue was filtered off,
dried in a vacuum, then taken up in water and chromatographed on SP
Sephadex.RTM. C-25. The product fractions free from sodium sulfate
were lyophilized and gave
4-oxo-5-[3-[4-oxo-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-4H-1-
benzopyran-5-yloxy]-2-sulfooxy-propoxy]-4H-1-benzopyran-2-carboxylic
acid 2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide undecasodium salt,
[a]-4.8.degree. (c 0.6; water).
EXAMPLE 2
A. 184 mg of cyanuric chloride, 543.5 mg of D-glucamine and 450 mg
of potassium carbonate were stirred at room temperature in 10 ml of
water for three days. The thus-obtained crude product was thereupon
chromatographed on LiChroprep RP-18 silica gel with water and
subsequently with water containing an increasing amount of
methanol. The relevant fractions were lyophilized;
N,N',N"-(1,3,5-triazine-2,4,6-triyl)-tris-(1-amino-1-desoxy-D-glucitol)
was thus obtained as a colorless powder, MS: m/z 619.2
([M+H].sup.+).
B. The
N,N',N"-(1,3,5-triazine-2,4,6-triyl)-tris-(1-amino-1-desoxy-D-glucitol)
obtained above was converted analogously to Example 1.b. into
N,N',N"-(1,3,5-triazine-2,4,6-triyl)-tris-(1-amino-1-desoxy-2,3,4,5,6-pent
a-O-sulfo-D-glucitol) pentadecasodium salt, [a]-1.4.degree. (c 0.9;
water), MS: m/z 2126.0 (reconstructed M), (tetradecasodium salt
monosulfonic acid).
EXAMPLE 3
A. 2.5 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
(E.P. 56575 A1, Bayer AG/CA 98(7)(1982):54399d), 2.4 g of methyl
(E)-3-(4-hydroxy-phenyl)-acrylate and 1.85 g of finely ground
anhydrous potassium carbonate were suspended in 30 ml of
dimethylformamide and stirred at 130.degree. C. under argon for 18
hours. The reaction mixture was subsequently diluted with water.
The crystals formed were filtered off and subsequently
chromatographed on silica gel with 5% ether in methylene chloride.
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-[(E)-4-(2-methoxycarbonyl-vinyl)-phe
nyl]-galactitol was thus obtained in the form of colorless
crystals. MS: m/z 582 ([M].sup.+).
B. 1.89 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[(E)-4-(2-methoxycarbonyl-vinyl)-phe
nyl]-galactitol, 30 ml of methanol and 30 ml of concentrated
aqueous sodium hydroxide solution were heated under reflux at
110.degree. C. for 18 hours. Thereupon, the majority of the
methanol was distilled off under reduced pressure. The residue was
diluted with ice-water and acidified with 1N aqueous hydrochloric
acid. The crystals thereby formed were filtered off and gave
1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3:4,5-di-O-isopropylidene-gal
actitol in the form of colorless crystals, MS: m/z 554
([M].sup.+).
C. 0.28 g of
1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3:4,5-di-O-isopropylidene-gal
actitol in 5 ml of dimethylformamide was treated with 0.1 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.20 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.19 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted several times with
water and evaporated at 40.degree.-50.degree. C. under reduced
pressure, the residue was treated with 6 ml of water and 0.5 ml of
triethylamine and the mixture was heated and filtered; there was
thus obtained
1,6-bis-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3:4,5-di-O-isopr
opylidene-galactitol as a colorless powder, MS: m/z 881.6
([M+H].sup.+).
D. 1.0 g of
1,6-bis-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3:4,5-di-O-isopr
opylidene-galactitol was suspended in 17 ml of dioxan, 2 ml of
trifluoroacetic acid and 5 ml of water and heated under reflux at
110.degree. C. for 4 hours. Thereupon, the reaction mixture was
concentrated to dryness;
1,6-bis-[(E)-4-(2-D-glucit-1-ylcarbamoyl-vinyl)-phenyl]-galactitol
thereby resulted as a colorless solid which was used directly in
the next step.
E. The
1,6-bis-[(E)-4-(2-D-glucit-1-ylcarbamoyl-vinyl)-phenyl]-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-vinyl]-
phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-1.7.degree. (c 0.7; water), MS: m/z 2229.0 (reconstructed
M).
EXAMPLE 4
A. 0.69 g of methyl 4'-hydroxy-biphenyl-4-carboxylate and 0.44 g of
finely ground potassium carbonate suspended in 2.5 ml of
dimethylformamide were treated with 0.54 g of
3,4-O-methoxymethylene-2,5-O-methylene-1,6-bis-O-(4-methyl-phenylsulfonyl)
-D-mannitol (B. Lamm et al., Acta Chem. Scand. B 41, 202 (1987)).
The reaction mixture was stirred at 130.degree. C. under argon for
18 hours. The reaction solution was subsequently poured into water.
The precipitate which separated was filtered off and
chromatographed on silica gel with methylene chloride/methanol.
There was thus obtained
1,6-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-3,4-O-methoxymethylene-2,5-O-
methylene-D-mannitol as a colorless solid, MS: m/z 656
([M].sup.+).
B. 1.0 g of
1,6-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-3,4-O-methoxymethylene-2,5-O-
methylene-D-mannitol dissolved in 20 ml of methanol was treated
with 6 ml of conc. sulfuric acid and heated under reflux for 16
hours. The reaction mixture was subsequently poured into water and
the separated crystals were filtered off. There was thus obtained
1,6-bis-O-(4'-methoxy-carbonyl-biphenyl-4-yl)-2,5-O-methylene-D-mannitol
as a colorless solid, MS: m/z 614 ([M].sup.+).
C. 0.67 g of
1,6-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-2,5-O-methylene-D-mannitol
was heated under reflux for 16 hours in 15 ml of concentrated
sodium hydroxide solution and 15 ml of methanol; thereupon the
mixture was evaporated and the residue was acidified with dilute
hydrochloric acid. The precipitate of
1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,5-O-methylene-D-mannitol
which thereby formed was filtered off, dissolved in 5 ml of acetic
anhydride and 5 ml of pyridine and stirred at room temperature for
16 hours. Now, the mixture was again evaporated, the residue was
poured into dilute hydrochloric acid and the mixture was filtered;
there was thus obtained
3,4-di-O-acetyl-1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,5-O-methylene-D-man
nitol in the form of colorless crystals, MS: m/z 669.4
([M-H].sup.-).
D. 0.78 g of
3,4-di-O-acetyl-1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,5O-methylene-D-mann
itol in 15 ml of dimethylformamide was treated with 0.26 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.47 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
reaction mixture was stirred at 0.degree.-5.degree. C. for a
further 2 hours. Subsequently, 0.49 g of D-glucamine was added and
the reaction mixture was stirred at room temperature for a further
18 hours. Thereupon, the mixture was diluted several times with
water and evaporated at 40.degree.-50.degree. C. under reduced
pressure, the residue was treated with 15 ml of pyridine and 15 ml
of acetic anhydride and the mixture was stirred for a further 18
hrs. Then, the reaction mixture was again concentrated and the
residue was treated with ice-water and 1N hydrochloric acid. The
thus-obtained precipitate was filtered off and dissolved in
methylene chloride, the solution was washed with water, dried over
magnesium sulfate and concentrated, and the residue was
chromatographed on silica gel with methylene chloride/methanol.
There was thus obtained
3,4-di-O-acetyl-1,6-bis-[4'-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylcarbamo
yl)-biphenyl-4-yl]-2,5-O-methylene-D-mannitol as a colorless solid,
MS: m/z 1417.4 ([M+H].sup.+).
E. 1.2 g of
3,4-di-O-acetyl-1,6-bis-[4'-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylcarbamo
yl)-biphenyl-4-yl]-2,5-O-methylene-D-mannitol were dissolved in 25
ml of methanol and 5 ml of tetrahydrofuran and treated with 1.2 ml
of 1 molar sodium methylate solution in methanol. The reaction
mixture was stirred at room temperature for 2.5 hours. The
precipitate which thereby formed was filtered off and washed with
methanol. There was thus obtained
1,6-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-2,5-O-methylene-D-mann
itol in the form of colorless crystals and was used directly in the
following reaction step.
F. The
1,6-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-2,5-O-methylene-D-mann
itol obtained above was converted analogously to Example 1.B. into
1,6-bis-[4'-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-biphenyl-4-yl
]-2,5-O-methylene-3,4-di-O-sulfo-D-mannitol dodecasodium salt,
[a]-7.6.degree. (c 0.7; water), MS: m/z 2137.0 (reconstructed
M).
EXAMPLE 5
A. 2.92 g of methyl 4'-hydroxy-biphenyl-4-carboxylate and 1.77 g of
finely ground potassium carbonate suspended in 25 ml of
dimethylformamide were treated with 2,0 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol.
The reaction mixture was stirred at 130.degree. C. under argon for
18 hours. The reaction solution was subsequently poured on to
ice-water and the separated precipitate was filtered off and
chromatographed on silica gel with methylene chloride/methanol.
There was thus obtained
2,3-O-isopropylidene-1,4-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-L-threit
ol as a colorless solid, MS: m/z 582 ([M].sup.+).
B. 1.77 g of
2,3-O-isopropylidene-1,4-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-L-threit
ol were heated under reflux for 18 hours in 40 ml of methanol and
40 ml of concentrated sodium hydroxide solution. Subsequently, the
methanol was distilled off. The residue was treated with ice-water,
acidified and the precipitate formed was filtered off; there was
thus obtained
1,4-bis-O-(4'-carboxy-biphenyl-4-yl)-2,3-O-isopropylidene-L-threitol
as a colorless solid, MS: m/z 554 ([M].sup.+).
C. 1.5 g of
1,4-bis-O-(4'-carboxy-biphenyl-4-yl)-2,3-O-isopropylidene-L-threitol
in 30 ml of dimethylformamide were treated with 0.6 ml of
4-methylmorpholine at 0.degree.-50.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 1.04 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine were added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 1.07 g of D-glucamine were added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted several times with
water and evaporated at 40.degree.-50.degree. C. under reduced
pressure, the residue was treated with 1 ml of triethylamine and 5
ml of water, the mixture was boiled briefly and the insoluble
precipitate was filtered off. There was thus obtained
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-2,3-O-isopropylidene-L
-threitol as a colorless solid, MS: m/z 881.2 ([M+H].sup.+).
D. 1.0 g of
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-2,3-O-isopropylidene-L
-threitol was suspended in 15 ml of dioxan, 1.5 ml of
trifluoroacetic acid and 5 ml of water and heated under reflux at
110.degree. C. for 4 hours. The reaction mixture was subsequently
concentrated to dryness. There was thus obtained
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-L-threitol as a
colorless solid, MS: m/z 841.6 ([M+H].sup.+).
E. The
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-L-threitol
obtained above was converted analogously to Example 1.B into
1,4-bis-O-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-biphenyl-4-y
l]-2,3-di-O-sulfo-L-threitol dodecasodium salt, [a]+0.85.degree. (c
0.7; water), MS: m/z 2065.0 (reconstructed M).
EXAMPLE 6
A. 0.6 g of
1,6-bis-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-vinyl
]-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt
(Example 3.E.) were exhaustively hydrogenated in 9 ml of distilled
water with the addition of 80 mg of palladium on charcoal (10%) in
a hydrogen atmosphere. Subsequently, the reaction mixture was
filtered over a 0.8.mu. cellulose filter and the filtrate was
lyophilized; there was thus obtained
1,6-bis-O-[4-[2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-ethyl]-ph
enyl]-2,3,4,5-tetra-O-sulfo-galactitol tetrasodium salt,
[a]-3.2.degree. (c 0.7; water), MS: m/z 2233.0 (reconstructed
M).
EXAMPLE 7
A. 2.0 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenyl-sulfonyl)-L-threitol,
2.3 g of methyl (E)-3-(4-hydroxy-phenyl)-acrylate and 1.77 g of
finely ground anhydrous potassium carbonate were suspended in 30 ml
of dimethylformamide. The reaction mixture was stirred at
130.degree. C. under argon for 18 hours. Subsequently, the reaction
mixture was diluted with water and extracted with methylene
chloride. The combined methylene chloride phases were dried over
magnesium sulfate and concentrated. The residue was chromatographed
on silica gel with 5% ether in methylene chloride. There was thus
obtained
2,3-O-isopropylidene-1,4-bis-[4-[(E)-2-methoxycarbonyl-vinyl]-phenyl]-L-th
reitol in the form of colorless crystals, MS: m/z 482
([M].sup.+).
B. 0.24 g of
2,3-O-isopropylidene-1,4-bis-[4-[(E)-2-methoxy-carbonyl-vinyl]-phenyl]-L-t
hreitol was stirred at room temperature in 2 ml of acetonitrile and
3 ml of 2N sodium hydroxide solution for 70 hours. The acetonitrile
was subsequently distilled off. The residue was treated with
ice-water, acidified and the precipitate formed was filtered off.
There was thus obtained
1,4-O-bis-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3-O-isopropylidene-L-threitol
as a colorless solid, MS: m/z 454 ([M].sup.+).
C. 1.0 g of
1,4-O-bis-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3-O-isopropylidene-L-threitol
in 20 ml of dimethylformamide was treated with 0.5 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.85 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.87 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted several times with
water and evaporated at 40.degree.-50.degree. C. under reduced
pressure, the residue was treated with 17 ml of pyridine and 17 ml
of acetic anhydride and the mixture was stirred for a further 18
hours. Then, the reaction mixture was again concentrated, the
residue was treated with ice-water and 1N hydrochloric acid and the
mixture was extracted with methylene chloride. The combined
methylene chloride phases were dried over magnesium sulfate and
concentrated, and the residue was chromatographed on silica gel
with methylene chloride/methanol. The product fraction was
dissolved in 30 ml of methanol and 7 ml of tetrahydrofuran, the
solution was treated with 2 ml of 1 molar sodium methylate solution
in methanol and the mixture was stirred at room temperature for 18
hours. The precipitate which thereby formed was filtered off after
the addition of a small amount of acetic acid and partial
distillation of the methanol. There was thus obtained
1,4-bis-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3-O-isopropyli
dene-L-threitol as a colorless solid, MS: m/z 781.5
([M+H].sup.+).
D. 0.33 g of
1,4-bis-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3-O-isopropyli
dene-L-threitol was suspended in 5 ml of dioxan, 1 ml of
trifluoroacetic acid and 1.5 ml of water and heated under reflux at
110.degree. C. for 1.5 hours. The reaction mixture was subsequently
concentrated to dryness. There was thus obtained
1,4-bis-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-L-threitol
as a colorless solid, MS: m/z 741.6 ([M+H].sup.+).
E. The
1,4-bis-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-L-threitol
obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-vinyl
]-phenyl]-2,3-di-O-sulfo-L-threitol dodecasodium salt,
[a]-0.86.degree. (c 0.7; water), MS: m/z 1966.0 (reconstructed
M).
EXAMPLE 8
A. 0.2 g of
1,4-bis-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-vinyl
]-phenyl]-2,3-di-O-sulfo-L-threitol dodecasodium salt was
exhaustively hydrogenated in 10 ml of distilled water with the
addition of 40 mg of palladium on charcoal (10%) in a hydrogen
atmosphere. Subsequently, the reaction mixture was filtered over a
0.8.mu. cellulose filter and the filtrate was lyophilized; there
was thus obtained
1,4-bis-O-[4-[2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-ethyl]-ph
enyl]-di-O-sulfo-L-threitol dodecasodium salt, [a]-0.17.degree.(c
0.6; water), MS: m/z 1970.0 (reconstructed M).
EXAMPLE 9
A. A solution of 4.91 g of
(4-methoxycarbonyl-benzyl)-triphenylphosphonium bromide in 50 ml of
tetrahydrofuran was treated at 0.degree.-5.degree. C. with the
exclusion of moisture and under argon with 1.91 g of
4-benzyloxy-benzaldehyde and subsequently slowly with 10 ml of 1N
sodium methylate solution in methanol. After stirring at room
temperature for 30 minutes, the reaction mixture was filtered over
Dicalite and concentrated, and the residue was chromatographed on
silica gel with hexane/ethyl acetate (3:1). There was thus obtained
methyl (Z)-4-[2-(4-benzyloxy-phenyl)-vinyl]-benzoate as a yellowish
solid, MS: m/z 344 ([M].sup.+).
B. 1.5 g of (Z)-4-[2-(4-benzyloxy-phenyl)-vinyl]-benzoate were
exhaustively hydrogenated in 20 ml of methanol and 20 ml of ethyl
acetate with the addition of 150 mg of palladium on charcoal (10%)
in a hydrogen atmosphere. The reaction mixture was subsequently
filtered over a 0.8.mu. cellulose filter and the filtrate was
concentrated; there was thus obtained methyl
4-[2-(4-hydroxy-phenyl)-ethyl]-benzoate as a colorless solid, MS:
m/z 256 ([M].sup.+).
C. 0.71 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol,
1.0 g of methyl 4-[2-(4-hydroxy-phenyl)-ethyl]-benzoate and 0.54 g
of finely ground anhydrous potassium carbonate were suspended in 20
ml of dimethylformamide and stirred at 130.degree. C. under argon
for 18 hours. Subsequently, the reaction mixture was diluted with
water and extracted with ethyl acetate. The combined ethyl acetate
phases were dried over magnesium sulfate and concentrated. The
residue was chromatographed on silica gel with 5% ether in
methylene chloride. There was thus obtained
2,3-O-isopropylidene-1,4-bis-O-[4-[2-(4-methoxycarbonyl-phenyl)-ethyl]-phe
nyl]-L-threitol in the form of colorless crystals, MS: m/z 638
([M].sup.+).
D. 0.7 g of
2,3-O-isopropylidene-1,4-bis-O-[4-[2-(4-methoxycarbonyl-phenyl)-ethyl]-phe
nyl]-L-threitol was stirred under reflux for 18 hours in 20 ml of
methanol and 20 ml of concentrated sodium hydroxide solution. The
methanol was subsequently distilled off. The residue was treated
with ice-water, acidified with dilute hydrochloric acid and the
precipitate formed was filtered off; there was thus obtained
1,4-bis-O-[4-[2-(4-carboxy-phenyl)-ethyl]-phenyl]-2,3-O-isopropylidene-L-t
hreitol as a colorless solid, MS: m/z 609.4 ([M-H].sup.-).
E. 0.52 g of
1,4-bis-O-[4-[2-(4-carboxyphenyl)-ethyl]-phenyl]-2,3-O-isopropylidene-L-th
reitol in 10 ml of dimethylformamide was treated with 0.21 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.33 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.34 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with 10 ml of water and 0.5
ml of triethylamine and the mixture was boiled briefly and
filtered. The residue which was thereby obtained was triturated in
20 ml of methanol and 20 ml of methylene chloride and again
filtered. There was thus obtained
1,4-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-2,3-O-iso
propylidene-L-threitol as a colorless solid, MS: m/z 959.6
([M+Na].sup.+).
F. 0.52 g of
1,4-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-2,3-O-iso
propylidene-L-threitol was suspended in 7 ml of dioxan, 2 ml of
trifluoroacetic acid and 3 ml of water and heated under reflux at
110.degree. C. for 18 hours. Subsequently, the reaction mixture was
concentrated to dryness, the residue was treated with 6 ml of
acetic anhydride and 6 ml of pyridine and the mixture was stirred
at room temperature for 18 hours. Then, the reaction mixture was
again concentrated and the residue was treated with ice-water and
1N hydrochloric acid. The precipitate which thereby formed was
filtered off and chromatographed on silica gel with methylene
chloride/isopropanol. There was thus obtained 2,3-
di-O-acetyl-1,4-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylcarb
amoyl)-phenyl]-ethyl]-phenyl]-L-threitol as a colorless solid, MS:
m/z 1424.9 ([M+Na].sup.+).
G. 0.36 g of
2,3-di-O-acetyl-1,4-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yl
carbamoyl)-phenyl]-ethyl]-phenyl]-L-threitol was dissolved in 5 ml
of ethanol and 5 ml of tetrahydrofuran, treated with 0.4 ml of 1
molar sodium methylate solution in methanol and stirred at room
temperature for 18 hours. The precipitate which thereby formed was
filtered off. There was thus obtained
1,4-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-L-threito
l as a colorless solid, MS: m/z 919.3 ([M+Na].sup.+).
H. The
1,4-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-L-threito
l obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-phenyl
]-ethyl]-phenyl]-2,3-di-O-sulfo-L-threitol dodecasodium salt,
[a]-0.57.degree. (c 0.7; water).
EXAMPLE 10
A. 1,4-Bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-D-threitol
was obtained as a colorless solid, MS: m/z 864.6 ([M+Na]+),
analogously to Example 5.A.-D. from methyl
4'-hydroxy-biphenyl-4-carboxylate and
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-D-threitol
in place of
2,3-O-isopropylidene-1,4-bis-O-(4-methylphenylsulfonyl)-L-threitol
via the following intermediates:
2,3-O-Isopropylidene-1,4-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-D-threito
l, colorless solid, MS: m/z 582 ([M].sup.+);
1,4-bis-O-(4'-carboxy-biphenyl-4-yl)-2,3-O-isopropylidene-D-threitol,
colorless solid, MS: m/z 553.5 ([M-H].sup.-);
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-2,3-O-isopropylidene-D-
threitol, colorless solid, MS: m/z 881.5 ([M+H].sup.+).
B. The
1,4-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-D-threitol
obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-biphenyl-4-y
l]-2,3-di-O-sulfo-D-threitol dodecasodium salt, [a]-9.80.degree. (c
0.8; water), MS: m/z 2066.0 (reconstructed M).
EXAMPLE 11
A.
1,6Bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-galactitol
was obtained as a colorless solid, MS: m/z 979.5 ([M+Na].sup.+),
analogously to Example 9.C.-9.G. from methyl
4-[2-(4-hydroxy-phenyl)-ethyl]-benzoate and
2,3:4,5-di-0-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
in place of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol
via the following intermediates:
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-[4-[2-(4-methoxycarbonyl-phenyl)-ethy
l]-phenyl]-galactitol, colorless solid, MS: m/z 738
([M].sup.+);
1,6-bis-O-[4-[2-(4-carboxy-phenyl)-ethyl]-phenyl]-2,3:4,5-di-O-isopropylide
ne-galactitol, colorless solid, MS: m/z 709.4 ([M-H].sup.-);
1,6-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-2,3:4,5-di
-O-isopropylidene-galactitol, colorless solid, MS: m/z 1037,6
([M+H].sup.+);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-acetyl-D-gluci
t-1-ylcarbamoyl)-phenyl)-ethyl]-phenyl]-galactitol, colorless
solid, MS: m/z 773.8 ([M+2H].sup.2+).
B. The
1,6-bis-O-[4-[2-(4-D-glucit-1-ylcarbamoyl-phenyl)-ethyl]-phenyl]-galactito
l obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[4-[2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-phenyl
]-ethyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt, [a]-3.3.degree. (c 0.6; water), MS: m/z 2385.0 (reconstructed
M).
EXAMPLE 12
A. 1.33 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
, 1.6 g of methyl 4'-hydroxy-biphenyl-4-carboxylate and 0.97 g of
finely ground anhydrous potassium carbonate were suspended in 20 ml
of dimethylformamide and stirred at 130.degree. C. for 18 hours
under argon. The reaction mixture was subsequently diluted with
water and the thus-formed crystals were filtered off. There was
thus obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-(4'-methoxycarbonyl-biphenyl-4-yl)-gal
actitol in the form of colorless crystals, MS: m/z 682
([M].sup.+).
B. 1.2 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-(4'-methoxy-carbonyl-biphenyl-4-yl)-ga
lactitol, 25 ml of methanol and 25 ml of concentrated aqueous
sodium hydroxide solution were heated under reflux at 110.degree.
C. for 18 hours. Thereupon, the majority of the methanol was
distilled off under reduced pressure, the residue was diluted with
ice-water, acidified with dilute aqueous hydrochloric acid and the
crystals which thereby formed were filtered off. There was thus
obtained
1,6-bis-(4'-carboxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-galactitol
in the form of colorless crystals, MS: m/z 653.5 ([M-H].sup.-).
C. 1.0 g of
1,6-bis-(4'-carboxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-galactitol
was suspended in 17 ml of dioxan, 4 ml of trifluoroacetic acid and
5 ml of water and heated under reflux at 110.degree. C. for 17
hours. Thereupon, the reaction mixture was concentrated, and the
residue was treated with methanol and filtered. There was thus
obtained 1,6-bis-(4'-carboxy-biphenyl-4-yl)-galactitol as a
colorless solid, elementary analysis calculated for C.sub.32
H.sub.30 O.sub.10 x0.31H.sub.2 O: C=66.25%, H =5.32%: found:
C=66.12%, H=5.24%.
D. 0.8 g of 1,6-bis-(4'-carboxy-biphenyl-4-yl)-galactitol was
stirred at 100.degree. C. for 5 hours in a mixture of 20 ml of
acetic anhydride and 20 ml of pyridine. Thereupon, the reaction
mixture was concentrated, the residue was treated with ice-water
and dilute hydrochloric acid and the thus-formed precipitate was
filtered off. There was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-galactitol
as a colorless solid, MS: m/z 741.4 ([M-H].sup.-).
E. 0.84 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-galactitol
in 20 ml of dimethylformamide was treated with 0.3 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.44 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.45 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted several times with
water and evaporated at 40.degree.-50.degree. C. under reduced
pressure, the residue was treated with 12 water and 0.5 ml of
triethylamine and the mixture was heated and filtered. For further
purification, the thus-obtained crude
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)
-galactitol was treated with 10 ml of pyridine and 10 ml of acetic
anhydride and stirred at room temperature for 24 hours. Then, this
reaction mixture was concentrated, the residue was treated with
ice-water and 1N hydrochloric acid and the mixture was extracted
with methylene chloride. The combined methylene chloride phases
were dried over magnesium sulfate, concentrated and the residue was
chromatographed on silica gel with methylene chloride/isopropanol.
There was obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4'-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-
ylcarbamoyl)-biphenyl-4-yl]-galactitol as a colorless solid, MS:
m/z 1489.4 ([M+H].sup.+).
F. 0.6 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4'-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-
ylcarbamoyl)-biphenyl-4-yl]-galactitol was dissolved in 5 ml of
methanol and 5 ml of tetrahydrofuran, treated with 0.4 ml of 1
molar sodium methylate solution in methanol and stirred at
60.degree. C. for 2 hours and at room temperature for 18 hours. The
precipitate which thereby formed was filtered off. There was
obtained
1,6-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-galactitol as a
colorless solid, MS: m/z 923.2 ([M+Na].sup.+).
G. The
1,6-bis-O-(4'-D-glucit-1-ylcarbamoyl-biphenyl-4-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[4'-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-biphenyl-4-
yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-2.4.degree. (c 0.7; water), MS: m/z 2330.0 (reconstructed
M).
EXAMPLE 13
A. 1,4-Bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threitol
was obtained as a colorless solid, MS: m/z 789.7 ([M+H].sup.+),
analogously to Example 5.A.-D. from methyl
3-hydroxy-naphthalene-2-carboxylate and
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol
via the following intermediates:
2,3-0-isopropylidene-1 ,4-bis-O-(3-
methoxycarbonyl-naphthalen-2-yl)-L-threitol, colorless solid, MS:
m/z 530 ([M].sup.+);
1,4-bis-O-(3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threitol,
colorless solid, MS: m/z 501.4 ([M-H].sup.-);
1,4-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-2,3-O-isopropylidene-L
-threitol, colorless solid, MS: m/z 830.0 ([M+H].sup.+).
B. The
1,4-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threitol
obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphtalen-2-
yl]-2,3-di-O-sulfo-L-threitol dodecasodium salt, [a]-3.9.degree. (c
0.7; water), MS: m/z 2013.5 (reconstructed M).
EXAMPLE 14
A. 1,6-Bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol
was obtained as a colorless solid, MS: m/z 849.7 ([M+H].sup.+),
analogously to Example 12.A.-F. from methyl
3-hydroxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-(2-methoxycarbonyl-naphthalen-2-yl)-g
alactitol, yellowish solid, MS: m/z 630 ([M].sup.+);
1,6-bis-O-(3-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galactito
l, colorless solid, MS: m/z 601.3 ([M-H].sup.-);
1,6-bis-O-(3-carboxy-naphthalen-2-yl)-galactitol, colorless solid,
MS: m/z 545.3 ([M+Na].sup.+);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-naphthalen-2-yl)-galactitol,
colorless solid, MS: m/z 713.4 ([M+Na].sup.+);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)
-galactitol, colorless solid, MS: m/z 1017.6 ([M+H].sup.+).
B. The
1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-2
-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-6.3.degree. (c 0.7; water), MS: m/z 2277.5 (reconstructed
M).
EXAMPLE 15
A. 0.4 g of bis-(4-hydroxy-phenyl)-methane dissolved in 8 ml of
acetonitrile was treated under argon with 0.3 g of powdered
potassium carbonate and 0.4 g of tert.-butyl bromoacetate and
stirred at room temperature for 2.5 hours. Subsequently, a further
0.13 g of tert.-butyl bromoacetate was added and the mixture was
stirred at room temperature for 70 hours. Thereupon, the reaction
mixture was concentrated and the residue was chromatographed on
silica gel with methylene chloride/ether (95:5); there was thus
obtained tert.-butyl 4-(4-hydroxy-benzyl)-phenoxyacetate as a
colorless solid, MS: m/z 314 ([M].sup.+).
B.
1,4-Bis-O-[4-(4-D-glucit-1-ylcarbamoylmethoxy-benzyl)-phenyl]-L-threitol
was obtained as a colorless solid, MS: m/z 952.4 ([M+Na].sup.+),
analogously to Example 12.A.-F. from tert.-butyl
4-(4-hydroxy-benzyl)-phenoxyacetate and
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenylsulfonyl)-L-threitol
via the following intermediates:
1,4-bis-O-[4-(4-tert.-butoxycarbonylmethoxy-benzyl)-phenyl]-2,3-O-isopropyl
idene-L-threitol, colorless solid, which was processed without
further characterization;
1,4-bis-O-[4-(4-carboxymethoxy-benzyl)-phenyl)-2,3-O-isopropylidene-L-threi
tol, colorless solid, MS: m/z 660.5 ([M+NH.sub.4 ].sup.+);
1,4-bis-O-[4-(4-carboxymethoxy-benzyl)-phenyl]-L-threitol,
colorless solid, MS: m/z 625.5 ([M+Na].sup.+);
2,3-di-O-acetyl-1,4-bis-O-[4-(4-carboxymethoxy-benzyl)-phenyl]-L-threitol,
brownish, amorphous solid, MS: m/z 685.4 ([M-H].sup.-);
2,3-di-O-acetyl-1,4-bis-O-[4-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylcarb
amoylmethoxy)-benzyl]-phenyl]-L-threitol, colorless amorphous
solid, MS: m/z 1456.8 ([M+Na].sup.+).
C. The
1,4-bis-O-[4-(4-D-glucit-1-ylcarbamoylmethoxy-benzyl)-phenyl]-L-threitol
obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[4-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoylmethoxy)-be
nzyl]-phenyl]-2,3-di-O-sulfo-L-threitol dodecasodium salt,
[a]+0.50.degree. (c 0.6; water), MS: m/z 2154.0 (reconstructed
M).
EXAMPLE 16
A. 1,6-Bis-O-(6-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol
was obtained as a reddish solid, MS: m/z 871.5 ([M+Na].sup.+),
analogously to Example 3.A.-D. from methyl
6-hydroxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-(6-methoxycarbonyl-naphthalen-2-yl)-g
alactitol, colorless solid, MS: m/z 630 ([M].sup.+);
1,6-bis-O-(6-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galactito
l, colorless solid, MS: m/z 601.3 ([M-H].sup.-);
1,6-bis-O-(6-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-2,3:4,5-di-O-isopropyl
idene-galactitol, colorless solid, MS: m/z 929.7 ([M+H].sup.+).
B. The
1,6-bis-O-(6-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol was
converted analogously to Example 1.B. into
1,6-bis-O-[6-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl-carbamoyl)-naphthalen-
2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-4.1.degree. (c 0.7; water)
EXAMPLE 17
A. 100 ml of sodium methylate solution in methanol (prepared with
2.6 g of sodium) followed by 22.29 g of 4-chloromethyl-biphenyl
were added while stirring and with the exclusion of moisture to
16.82 g of methyl 3,5-dihydroxy-benzoate dissolved in 120 ml of
methanol and the mixture was stirred at 90.degree. C. for 4 hours.
Thereupon, the reaction mixture was concentrated, and the residue
was partitioned between methylene chloride and dilute hydrochloric
acid. The combined methylene chloride phases were dried over
magnesium sulfate and concentrated, and the residue was
chromatographed on silica gel with methylene chloride/methanol. The
thus-obtained product fraction was recrystallized from methylene
chloride. There was thus obtained methyl
3-biphenyl-4-ylmethoxy-5-hydroxy-benzoate in the form of colorless
crystals, MS:m/z 334 ([M].sup.+).
B.
1,6-Bis-O-(3-biphenyl-4-ylmethoxy-5-D-glucit-1-ylcarbamoyl-phenyl)-2,3:4,5
-di-O-isopropylidene-galactitol was obtained in the form of
colorless crystals, MS: m/z 1215.3 ([M+Na].sup.+), from methyl
3-biphenyl-4-ylmethoxy-5-hydroxy-benzoate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
1,6-bis-O-(3-biphenyl-4-ylmethoxy-5-methoxycarbonyl-phenyl)-2,3:4,5-di-O-is
opropylidene-galactitol, colorless solid, which was processed
without further characterization;
1,6-bis-O-(3-biphenyl-4-ylmethoxy-5-carboxy-phenyl)-2,3:4,5-di-O-isopropyli
dene-galactitol, colorless solid, MS: m/z 865.2 ([M-H].sup.-).
C. 0,2 g of
1,6-bis-O-(3-biphenyl-4-ylmethoxy-5-D-glucit-1-ylcarbamoyl-phenyl)-2,3:4,5
-di-O-isopropylidene-galactitol was suspended in 2 ml of dioxan,
0.5 ml of trifluoroacetic acid and 0.7 ml of water and stirred at
room temperature for 72 hours. Thereupon, the reaction mixture was
concentrated and the residue was treated with methanol and
filtered. There was thus obtained
1,6-bis-O-(3-biphenyl-4-ylmethoxy-5-D-glucit-1-ylcarbamoyl-phenyl)-galacti
tol as a colorless solid, MS: m/z 1114.4 ([M+H].sup.+).
D. The
1,6-bis-O-(3-biphenyl-4-ylmethoxy-5-D-glucit-1-ylcarbamoyl-phenyl)-galacti
tol obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[3-biphenyl-4-ylmethoxy-5-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
carbamoyl)-phenyl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt, [a]-2,4.degree. (c 0.7; water), MS: m/z 2512.0 (reconstructed
[M-Na]).
EXAMPLE 18
A. 1,4-Bis-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threitol was
obtained as a colorless solid, MS: m/z 689.3 ([M+H].sup.+),
analogously to Example 3.A.-D. from methyl 4-hydroxy-benzoate and
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol
via the following intermediates:
2,3-O-Isopropylidene-1,4-bis-O-(4-methoxycarbonyl-phenyl)-L-threitol,
colorless solid, MS: m/z 430 ([M].sup.+);
1,4-bis-O-(4-carboxy-phenyl)-2,3-O-isopropylidene-L-threitol,
colorless solid, MS: m/z 402 ([M].sup.+);
1,4-bis-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-2,3-O-isopropylidene-L-threitol
, colorless solid, MS: m/z 729.4 ([M+H].sup.+).
B. The 1,4-bis-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threitol
obtained above was converted analogously to Example 1.B. into
1,4-bis-O-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-phenyl]-2,3-
di-O-sulfo-L-threitol dodecasodium salt, [a]-3.1.degree. (c 0.7;
water), MS: m/z 1913.5 (reconstructed M).
EXAMPLE 19
A. 1,6-Bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-1-yl)-galactitol
was obtained as a colorless solid, MS: m/z 872.4 ([M+Na].sup.+),
analogously to Example 3.A.-D. from ethyl
4-hydroxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-(3-ethoxycarbonyl-naphthalen-1-yl)-ga
lactitol, colorless solid, MS: m/z 658 ([M].sup.+);
1,6-bis-O-(3-carboxy-naphthalen-1-yl)-2,3:4,5-di-O-isopropylidene-galactito
l, colorless solid, MS: m/z 602 ([M].sup.+);
1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-1-yl)-2,3:4,5-di-O-isopropyl
idene-D-galactitol, colorless solid, MS: m/z 9518
([M+Na].sup.+)
B. The
1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-1-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naphthalen-1
-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-1.2.degree. (c 0.5; water), MS: m/z 2277.0 (reconstructed
M).
EXAMPLE 20
A. 6.55 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid were
dissolved in 20 ml of dimethylformamide, treated with 5.5 g of
sodium hydrogen carbonate and 4.0 ml of dimethyl sulfate and
stirred at 90.degree. C. under argon for 10 minutes. Subsequently,
the reaction mixture was poured on to ice-water and extracted with
ether. The combined ether phases were washed with water, dried over
magnesium sulfate and concentrated. The thus-obtained residue was
recrystallized from ethyl acetate/hexane. Methyl
3-hydroxy-7-methoxy-naphthalene-2-carboxylate with m.p. 138.degree.
C. was thus obtained.
B.
1,6-Bis-O-(3-D-glucit-1-ylcarbamoyl-6-methoxy-naphthalen-2-yl)-galactitol
was obtained as a colorless solid, MS: m/z 909.3 ([M+H].sup.+),
analogously to Example 12.A.-F. from methyl
3-hydroxy-7-methoxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropyl-idene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactito
l via the following intermediates:
1,6-bis-O-(6-methoxy-3-methoxycarbonyl-naphthalen-2-yl)-2,3:4,5-di-O-isopro
pylidene-galactitol, colorless solid, MS: m/z 690 ([M].sup.+);
1,6-bis-O-(3-carboxy-6-methoxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene
-galactitol, colorless solid, MS: m/z 661.2 ([M-H].sup.-);
1,6-bis-O-(3-carboxy-6-methoxy-naphthalen-2-yl)-galactitol,
colorless solid, MS: m/z 581.2 ([M-H].sup.-);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-6-methoxy-naphthalen-2-yl)-gala
ctitol, colorless solid, MS: m/z 749.1 ([M-H].sup.-);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-6-methoxy-naphth
alen-2-yl)-galactitol, colorless solid, MS: m/z 1077.4
([M+H].sup.+).
C. The
1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-6-methoxy-naphthalen-2-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[6-methoxy-3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-na
phthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt, [a]-5.7.degree. (c 0.6; water), MS: m/z 2337.5 (reconstructed
M).
EXAMPLE 21
A. Methyl 3-hydroxy-5-methoxy-naphthalene-2-carboxylate with m.p.
182.degree. C. was obtained analogously to Example 20.A. from
3-hydroxy-5-methoxy-naphthalene-2-carboxylic acid.
B.
1,6-Bis-O-(3-D-glucit-1-ylcarbamoyl-8-methoxy-naphthalen-2-yl)-galactitol
was obtained as a colorless solid, MS: f/z 909.2 ([M+H].sup.+),
analogously to Example 12.A.-F. from methyl
3-hydroxy-5-methoxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
2,3:4,5-Di-O-isopropylidene-1,6-bis-O-(8-methoxy-3-methoxy-carbonyl-naphtha
len-2-yl)-galactitol, colorless solid, MS: m/z 690 ([M].sup.+);
1,6-bis-O-(3-carboxy-8-methoxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene
-galactitol, MS: m/z 661.1 ([M-H].sup.-);
1,6-bis-O-(3-carboxy-8-methoxy-naphthalen-2-yl)-galactitol,
colorless solid, MS: m/z 581.2 ([M-H].sup.-);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-5-methoxy-naphthalen-2-yl)-gala
ctitol, colorless solid, MS: m/z 749.1 ([M-H].sup.-);
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[8-methoxy-3-(2,3,4,5,6-penta-O-acetyl-D-g
lucit-1-ylcarbamoyl)-naphthalen-2-yl]-galactitol, colorless solid,
MS: m/z 1497.2 ([M+H].sup.+).
C. The
1,6-bis-O-(3-D-glucit-1-ylcarbamoyl-8-methoxy-naphthalen-2-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[8-methoxy-3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-na
phthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium
salt, [a]-9.30 (c 0,7; water), MS: m/z 2337.0 (reconstructed
M).
EXAMPLE 22
A. 25.0 g of 3,7-dihydroxy-naphthalene-2-carboxylic acid and 22.5 g
of sodium hydrogen carbonate were dissolved in 125 ml of
dimethylformamide, treated with 16.5 ml of dimethyl sulfate and
stirred at 85.degree. C. for 20 minutes. Thereupon, the reaction
mixture was poured on to ice-water. The crystals formed were
filtered off, there being thus obtained methyl
3,7-dihydroxy-naphthalene-2-carboxylate as a yellowish solid, MS
m/z 218 ([M].sup.+).
B. 6.5 g of methyl 3,7-dihydroxy-naphthalene-2-carboxylate and 11.3
g of (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate
were stirred at 80.degree. C. for 60 hours in 50 ml of acetonitrile
with the addition of 5.4 g of potassium carbonate. The reaction
mixture was poured on to ice-water and extracted with ether. The
combined ether phases were washed with water, dried over magnesium
sulfate, filtered and evaporated; the thus-obtained residue was
chromatographed on silica gel with hexane/ether, there being thus
obtained methyl
7-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-hydroxy-naphthalene-2-car
boxylate as a yellowish solid, MS: m/z 332 ([M].sup.+).
C.
1,6-Bis-O-[6-[(R)-2,3-dihydroxy-propoxy]-3-D-glucit-1-ylcarbamoyl-naphthal
en-2-yl]-galactitol was obtained as a colorless solid, MS m/z
1051.3 ([M+Na].sup.+), analogously to Example 3.A.-D. from methyl
7-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-hydroxy-naphthalene-2-car
boxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
1,6-bis-O-[6-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-methoxycarbonyl
-naphthalen-2-yl]-2,3:4,5-di-O-isopropylidene-galactitol, colorless
solid, MS: m/z 891.3 ([M+H].sup.+);
1,6-bis-O-[3-carboxy-6-[(S)-2,2-dimethyl-[1,3]dioxolan-4-yl]-naphthalen-2-y
l]-2,3:4,5-di-O-isopropylidene-galactitol, colorless solid, MS: m/z
861.4 ([M-H].sup.-);
1,6-bis-O-[6-[(S)-2,2-dimethyl-[1,3]dioxolan-4-yl]-3-D-glucit
1-ylcarbamoyl-naphthalen-yl]-2,3:4,5-di-O-isopropylidene-galactitol,
colorless solid, MS: m/z 1211.6 ([M+Na].sup.+);
D. The 1,6-bis-O-[6-[(R)-2,3-dihydroxy-propoxyl-3-D-glucit-1-
ylcarbamoyl-naphthalen-2-yl]-galactitol obtained above was
converted analogously to Example 1.B. into
1,6-bis-O-[6-[(S)-2,3-bis-sulfooxy-propoxy]-3-(2,3,4,5,6-penta-O-sulfo-D-g
lucit
1-ylcarbamoyl)-naphthalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol
octadecasodium salt, [a]-4.6.degree. (c 0.7; water), MS: m/z 2864.0
(reconstructed M).
EXAMPLE 23
A. Methyl 7-bromo-3-hydroxy-naphthalene-2-carboxylate was obtained
as a yellowish solid, MS m/z 280.282 ([M].sup.+), analogously to
Example 22.A. from 7-bromo-3-hydroxy-naphthalene-2-carboxylic acid
(R. A. Murphy et al., J. Med. Chem. 33, 171 (1990)).
B.
1,6-Bis-O-(6-bromo-3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol
was obtained as a colorless solid, MS m/z 1029.1 ([M+Na].sup.+),
analogously to Example 3.A.-D. from methyl
7-bromo-3-hydroxy-naphthalene-2-carboxylate and
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
via the following intermediates:
1,6-bis-O-(6-bromo-3-methoxycarbonyl-naphthalen-2-yl)-2,3:4,5-di-O-isopropy
lidene-galactitol, colorless solid, MS: m/z 773 ([M-CH.sub.3
].sup.+);
1,6-bis-O-(6-bromo-3-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-g
alactitol, colorless solid, MS: m/z 783.2 ([M+Na].sup.+);
1,6-bis-O-(6-bromo-3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-2,3:4,5-di-O-i
sopropylidene-galactitol, colorless solid, which was processed
without further purification.
C. The
1,6-bis-O-(6-bromo-3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[6-bromo-3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naph
thalen-2-yl]-2,3,4,5-tetra-O-sulfo-galactitol tetradecasodium salt,
[a]-15.4.degree. (c 0.7; water).
EXAMPLE 24
A. A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of
tris-hydroxymethyl-methylamine in 50 ml of methanol was heated
under reflux for 6 days and then concentrated. The residue was
purified by chromatography over silica gel with ethyl
acetate/methanol/water as the eluent and gave
N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide,
[a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3
([M+H].sup.+).
B. A suspension of 0.36 g of
N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide and
2.23 g of sulfur trioxide-trimethylamine complex in 10 ml of
absolute dimethylformamide was stirred at 70.degree. C. for 24
hours. After cooling, the mixture was treated with 2.63 g of sodium
acetate in 50 ml of methanol. The precipitate was filtered off
under suction, washed with methanol and dried. The residue was
taken up in water and chromatographed on Sephadex.RTM. LH20 and SP
Sephadex.RTM. C-25. The product fractions were lyophilized and gave
2,3-di-O-sulfo-N,N'-bis-(2-sulfooxy-1,1-bis-sulfooxymethyl-ethyl)-L-tartar
amide octasodium salt, [a]+31.20 (c 0.5; water), MS: m/z 1172
(reconstructed M).
EXAMPLE 25
A. Dimethyl L-tartrate and D-glucamine were reacted with one
another as described under Ex. 24.A. and gave L-tartaric acid
N,N'-bis-D-glucit-1-yl-amide, [[a]+52.0.degree. (c 0.5; dimethyl
sulfoxide), MS: m/z 477.6 ([M+H].sup.+).
B. A suspension of 0.48 g of L-tartaric acid
N,N'-bis-D-glucit-1-yl-amide and 3.34 g of sulfur
trioxide-trimethylamine complex in 15 ml of absolute
dimethylformamide was stirred at 70.degree. C. for 18 hours. After
cooling, the upper phase was decanted off. The residue was treated
with 1.97 g of sodium acetate in 20 ml of water and evaporated, and
the residue was then taken up several times in water and
evaporated. The thus-obtained residue was taken up in water and
chromatographed on Sephadex.RTM. LH20 and SP Sephadex.RTM. C-25.
The product fractions were lyophilized and gave
N,N'-bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)-di-O-sulfo-L-tartaramide
dodecasodium salt, [a]+18.6.degree. (c 0.5; water), MS: m/z 1705
(reconstructed M).
EXAMPLE 26
A. A suspension of 2.0 g of dimethyl D-tartrate and 4.47 g of
D-glucamine in 50 ml of methanol was heated under reflux for 8
days, filtered off under suction and washed with methanol. The
suction filter material was dried and acetylated with 110 ml of
acetic anhydride in 220 ml of pyridine at room temperature for 18
hours. The reaction product was concentrated and the residue was
precipitated from water and dried to give
2,3-di-O-acetyl-N,N'-bis-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yl)-D-tartar
amide, [a]+10.4.degree. (c 0.5; dimethyl sulfoxide), MS: m/z 1003.5
([M+Na].sup.+).
B. A solution of 4.8 g of
2,3-di-O-acetyl-N,N'-bis-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yl)-D-tartar
amide in 50 ml of methanol and 50 ml of tetrahydrofuran was treated
with 4.8 ml of a 2% methanolic sodium methanolate solution and
stirred at room temperature for 5 hours. The resulting precipitate
was filtered off under suction, washed with methanol and dried at
60.degree. C. in a vacuum to give
N,N'-di-D-glucit-1-yl-D-tartaramide, MS: n/z 499.6
([M+Na].sup.+).
C. A suspension of 1.0 g of N,N'-di-D-glucit-1-yl-D-tartaramide and
9.07 g of sulfur trioxide-triethylamine complex in 50 ml of
absolute dimethylformamide was stirred at 45.degree. C. for 20
hours. After cooling, the mixture was concentrated in a high vacuum
and the residue was treated with a solution of 8.2 g of sodium
acetate in 90 ml of water and evaporated. The residue was treated
several times with water and again evaporated. The thus-obtained
residue was taken up in water and chromatographed on Sephadex.RTM.
LH20 and SP Sephadex.RTM. C-25. The product fractions were
lyophilized and gave
N,N'-bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)-2,3-di-O-sulfo-D-tartaram
ide dodecasodium salt, [a]-28.8.degree. (c 0.5; water), MS: m/z
1700.5 (reconstructed M).
EXAMPLE 27
A. Reaction of dimethyl meso-tartrate and D-glucamine as described
in Ex. 26.A. gave
2,3-di-O-acetyl-N,N'-bis-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yl)-meso-tar
taramide, [a].sup.+ 6.2.degree. (c 0.5; dimethyl sulfoxide), MS:
m/z 1003.8 ([M+Na].sup.+).
B. Deacetylation of
2,3-di-O-acetyl-N,N'-bis-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yl)-meso-tar
taramide as described in Ex. 26.B. gave
N,N'-di-D-glucit-1-yl-meso-tartaramide, MS: m/z 499.4
([M+Na].sup.+).
C. Sulfation of N,N'-di-D-glucit-1-yl-meso-tartaramide as described
in Ex. 26.C. gave
N,N'-bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)-2,3-di-O-sulfo-meso-tarta
ramide dodecasodium salt, [a]-4.6.degree. (c 0.5; water), MS: m/z
1700.5 (reconstructed M).
EXAMPLE 28
A. Reaction of dimethyl galactarate and
tris-hydroxymethyl-methylamine as described in Ex. 25.A. gave
N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-galactaramide, MS:
m/z 417.1 ([M+H].sup.+).
B. Sulfation of
N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-galactaramide as
described in Ex. 25.B. gave
2,3,4,5-tetra-O-sulfo-N,N'-bis-(2-sulfooxy-1,1-bis-sulfooxymethyl-ethyl)-g
alactaramide decasodium salt, MS: m/z 1436.0 (reconstructed M).
EXAMPLE 29
A. Reaction of dimethyl galactarate and D-glucamine as described in
Ex. 25.A. gave N,N'-di-D-glucit-1-yl-galactaramide,
[a]-14.4.degree. (c 0.5; water), MS: m/z 537.2 ([M+H].sup.+).
B. Sulfation of N,N'-di-D-glucit-1-yl-galactaramide as described in
Ex. 25.B. gave
N,N'-bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)-2,3,4,5-tetra-O-sulfo-gal
actaramide tetradecasodium salt, MS: m/z 1963.0 (reconstructed
M).
EXAMPLE 30
A. 15 g of 4-aminomethyl-benzylamine were dissolved in 600 ml of
methylene chloride and treated within 2.5 hours with a solution of
8.0 g of di-tert.-butyl dicarbonate in 80 ml of methylene chloride.
Thereupon, the separated precipitate was filtered off and discarded
and the mother liquor was evaporated. The thus-obtained residue was
chromatographed on silica gel with hexane/ethyl acetate/methanol;
there thus being obtained tert.-butyl
(4-aminomethyl-benzyl)-carbamate, MS: m/z 179
([M-tert.-butyl].sup.+).
B. 0.6 ml of diethyl D-tartrate and 1.81 g of tert.-butyl
(4-aminomethyl-benzyl)-carbamate were dissolved in 20 ml of ethanol
and heated under reflux at 85.degree. C. for 44 hours. After
cooling to 0.degree. C., the separated crystals were filtered off
and dried in a high vacuum; there was thus obtained
N,N'-bis-(4-tert.-butoxycarbonylamino-methyl-benzyl)-D-tartaramide,
MS: m/z 587.1 ([M+H].sup.+).
C. 0.594 g of
N,N'-bis-(4-tert.-butoxycarbonylaminomethyl-benzyl)-D-tartaramide
was dissolved in 0.8 ml of trifluoroacetic acid at 0.degree. C. and
subsequently stirred at room temperature for 5 hours; the mixture
was subsequently evaporated and the residue was treated with
methylene chloride/ether (1:1). The precipitate which formed was
filtered off. There was obtained
N,N'-bis-(4-aminomethyl-benzyl)-D-tartaramide di(trifluoroacetate),
MS: m/z 387.4 ([M+H].sup.+).
D. 0.69 g of N,N'-bis-(4-aminomethyl-benzyl)-D-tartaramide
di-(trifluoroacetate) was dissolved in 40 ml of ethanol, treated
with 0.47 ml of triethylamine and 0.48 g of D-gluconic acid
d-lactone and stirred at 85.degree. C. for 16 hours. After cooling,
the precipitate formed was filtered off, washed with ether and
dried in a high vacuum. There was thus obtained
N,N'-bis-(4-D-glucit-1-ylcarbamoylmethyl-benzyl)-D-tartaramide, MS
m/z 743.4 ([M+H].sup.+).
E. The
N,N'-bis-(4-D-glucit-1-ylcarbamoylmethyl-benzyl)-D-tartaramide
obtained above was converted analogously to Example 1.B. into
N,N'-bis-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl-carbamoylmethyl)-benzyl
]-di-O-sulfo-D-tartaramide dodecasodium salt, MS: m/z 1967.0
(reconstructed M).
EXAMPLE 31
A. 0.97 g of
1-O-(4-amino-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
(prepared as described in European Patent Application 95 100 180.9
of 9.1.95) and 0.27 g of benzene-1,3,5-tricarboxylic acid
trichloride were dissolved in 22 ml of methylene chloride, treated
with 1.0 ml of triethylamine at 5.degree. C. and stirred at room
temperature for 60 hours. After concentration, the crude product
was chromatographed on silica gel with methylene chloride and
methanol. There was obtained benzene-1,3,5-tricarboxylic acid
tris-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenylamide],
MS: m/z 1127 ([M+H].sup.+).
B. 0.95 g of benzene-1,3,5-tricarboxylic acid
tris-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenylamide]
was dissolved in 20 ml of dioxan, treated with 3 ml of
trifluoroacetic acid (35%) and stirred at reflux for 7 hours.
Subsequently, 50 ml of toluene were added twice and the mixture was
concentrated in a water-jet vacuum each time. The thus-obtained
residue was dried in a high vacuum at room temperature over
phosphorus pentoxide for 4 hours. There was thus obtained
benzene-1,3,5-tricarboxylic acid
tris-(4-D-arabinit-1-yloxy-phenylamide) which was used directly in
the next step.
C. 0.98 g of benzene-1,3,5-tricarboxylic acid
tris-(4-D-arabinit-1-yloxy-phenylamide) was reacted with sulfur
trioxiode-trimethylamine complex in analogy to Example 1.B. There
was thus obtained benzene-1,3,5-tricarboxylic acid
tris-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1yloxy)-phenylamide]
dodecasodium salt, MS: m/z 2110.0 (reconstructed M).
EXAMPLE 32
A. 18.2 g of 5-hydroxyisophthalic acid were stirred at reflux for
18 hours in 300 ml of methanol with the addition of 5 ml of
sulfuric acid (96%). After cooling to 5.degree. C., the mixture was
adjusted to pH 8 with saturated sodium bicarbonate solution and
then the methanol was distilled off in a water-jet vacuum. The
heterogeneous aqueous phase was exhaustively extracted with
methylene chloride; the organic phase was dried over magnesium
sulfate, filtered and concentrated. There was obtained dimethyl
5-hydroxy-isophthalate which was recrystallized from methylene
chloride/n-hexane, m.p. 159.degree.-161.degree. C.
B. 2.1 g of dimethyl 5-hydroxy-isophthalate and 2.9 g of
(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate were
stirred at reflux for 3 hours in 120 ml of dimethylformamide with
the addition of 6.9 g of potassium carbonate. The reaction mixture
was poured on to ice-water, extracted with methylene chloride, the
combined methylene chloride phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. There was obtained
dimethyl
(S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalate, MS:
m/z 324 ([M].sup.+).
C. 1.40 g of dimethyl
(S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalate were
stirred at room temperature for 16 hours with 4 ml of sodium
hydroxide solution (28%) in 50 ml of methanol. After neutralization
with 6N hydrochloric acid, the methanol was distilled off in a
water-jet vacuum. The residue was poured on to ice-water, extracted
with methylene chloride, the combined methylene chloride phases
were washed with water, dried over magnesium sulfate, filtered and
evaporated. There was obtained
(S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalic acid,
MS: m/z 296 ([M].sup.+).
D. 0.59 g, of
(S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalic acid
dissolved in 10 ml of acetonitrile was treated with 0.44 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.70 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 1.29 g of
1-O-(4-amino-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
dissolved in 30 ml of acetonitrile/dimethylformamide (2:1) was
added and the mixture was stirred at room temperature for a further
18 hours. After distillation of the solvent in a high vacuum, the
residue was chromatographed on silica gel with methylene chloride
and methanol. There was obtained
(S)-N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyl]-5
-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalamide, MS: m/z
907 ([M+H].sup.+).
E. 2.05 g of
(S)-N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyl]-5
-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalamide were
dissolved in 50 ml of dioxan, treated with 15 ml of trifluoroacetic
acid (70% in water) and stirred at reflux for 12 hours.
Subsequently, 50 ml of toluene were added twice and the mixture was
concentrated each time in a water-jet vacuum. The thus-obtained
residue was dried in a high vacuum at room temperature over
phosphorus pentoxide for 4 hours. There was obtained
(R)-N,N'-bis-(4-D-arabinit-1-yloxy-phenyl)-5-(2,3-dihydroxy-propoxy)-isoph
thalamide, MS: m/z 707 ([M+H].sup.+).
F. 1.05 g of
(R)-N,N'-bis-(4-D-arabinit-1-yloxy-phenyl)-5-(2,3-dihydroxy-propoxy)-isoph
thalamide were reacted with sulfur trioxide-trimethylamine complex
in analogy to Example 1.B. There was thus obtained
(S)-N,N'-bis-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1yloxy)-phenyl]-5-(2,3-b
is-sulfooxy-propoxy)-isophthalamide decasodium salt, MS: m/z,
1727.0 (reconstructed M).
EXAMPLE 33
A. 2.35 g of
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenylsulfonyl)-L-threitol
and 1.52 g of methyl 4-hydroxy-benzoate were stirred at reflux for
3 hours in 75 ml of dimethylformamide with the addition of 3.46 g
of potassium carbonate. The reaction mixture was poured on to
ice-water, extracted with methylene chloride, the combined
methylene chloride phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The crude product was
chromatographed on silica gel with methylene chloride and methanol.
There was obtained
2,3-O-isopropylidene-1,4-bis-O-(4-methoxycarbonyl-phenyl)-L-threitol,
MS: m/z 430 ([M].sup.+).
B. 1.81 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methoxycarbonyl-phenyl)-L-threitol
were stirred at 50.degree. C. for 20 hours in 50 ml of methanol
with the addition of 5 ml of sodium hydroxide solution (28%). The
reaction mixture was thereafter cooled to 10.degree. C., adjusted
to pH 2 with hydrochloric acid and the methanol was distilled off
in a water-jet vacuum. 100 ml of water were added to the residue,
the mixture was stirred in an ice bath for 1 hour, then filtered
and dried. There was obtained
1,4-bis-O-(4-carboxy-phenyl)-L-threitol, MS: m/z 361
([M-H].sup.-).
C. 1.33 g of 1,4-bis-O-(4-carboxy-phenyl)-L-threitol were stirred
at room temperature for 20 hours in 20 ml of pyridine with 3.8 ml
of acetic anhydride. The reaction mixture was poured on to
ice-water, extracted with methylene chloride, the combined
methylene chloride phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. There was obtained
2,3-di-O-acetyl-1,4-bis-O-(4-carboxy-phenyl)-L-threitol which was
recrystallized from methanol/methylene chloride, MS: m/z 387
([M-AcO].sup.-).
D. 0.89 g of
2,3-di-O-acetyl-1,4-bis-O-(4-carboxy-phenyl)-L-threitol dissolved
in 10 ml of acetonitrile was treated with 0.44 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.70 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 1.29 g of
1-O-(4-amino-phenyl)2,3:4,5-di-O-isopropylidene-D-arabinitol
dissolved in 30 ml of acetonitrile/dimethylformamide (2:1) were
added and the mixture was stirred at room temperature for a further
18 hours. After distillation of the solvent in a high vacuum, the
residue was chromatographed on silica gel with methylene chloride
and methanol. There was obtained
2,3-di-O-acetyl-1,4-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-
yloxy)-phenylcarbamoyl]-phenyl]-L-threitol, MS: m/z 1057
([M+H].sup.+).
E. 2.9 g of
2,3-di-O-acetyl-1,4-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-
yloxy)-phenylcarbamoyl]-phenyl]-L-threitol were dissolved in 40 ml
of dioxan, treated with 2.8 ml of trifluoroacetic acid and 5.6 ml
of distilled water and stirred under reflux for 3 hours;
subsequently 100 ml of toluene were added twice and the mixture was
concentrated in a water-jet vacuum each time. The thus-obtained
residue was dried in a high vacuum at room temperature over
phosphorus pentoxide for 4 hours. There was thus obtained
2,3-di-O-acetyl-1,4-bis-O-[4-(4-D-arabinit-1-yloxy-phenylcarbamoyl)-phenyl
]-L-threitol which was used directly in the next step.
F. 2.08 g of
2,3-di-O-acetyl-1,4-bis-O-[4-(4-D-arabinit-1-yloxy-phenylcarbamoyl)-phenyl
]-L-threitol were stirred at room temperature for 18 hours in 50 ml
of methanol with 1.0 g of potassium carbonate with the addition of
15 ml of water/dimethylformamide (2:1). The solvent was distilled
off in a high vacuum and the residue was then taken up in 50 ml of
water, filtered and the residue was dried. There was obtained
1,4-bis-O-[4-(4-D-arabinit-1-yloxy-phenylcarbamoyl)-phenyl]-L-threitol.
Elementary analysis calculated for C.sub.40 H.sub.48 N.sub.2
O.sub.16 : C=59.11%, H=5.95%, N=3.45%; found: C=58.69%, H=6.07%,
N=3.10%.
G. 1.20 g of
1,4-bis-O-[4-(4-D-arabinit-1-yloxy-phenyl-carbamoyl)-phenyl]-L-threitol
were reacted with sulfur trioxide-trimethylamine complex in analogy
to Example 1.B. There was thus obtained
1,4-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-phenyl-carbamoy
l]-phenyl]-2,3-di-O-sulfo-L-threitol decasodium salt, MS: m/z
1833.0 (reconstructed M).
EXAMPLE 34
A. 16.7 g of
2,5-O-methylene-1,6-bis-O-(4-methyl-phenyl-sulfonyl)-D-mannitol (B.
Lamm et al., Acta Chem. Scand. B 41, 202 (1987)) were stirred at
room temperature under argon for 16 hours with the addition of 0.1
g of p-toluenesulfonic acid in 80 ml of trimethyl orthoformate.
After neutralization with potassium carbonate and subsequent
filtration, the filtrate was concentrated. The residue was
recrystallized from methanol. There was obtained
3,4-O-methoxymethylene-2,5-O-methylene-1,6-bis-O-(4-methyl-phenylsulfonyl)
-D-mannitol, MS: m/z 545 ([M+H].sup.+).
B. 4.36 g of
3,4-O-methoxymethylene-2,5-O-methylene-1,6-bis-O-(4-methyl-phenylsulfonyl)
-D-mannitol were reacted with 2.44 g of methyl 4-hydroxy-benzoate
and worked up in analogy to Example 33.A. The crude product was
chromatographed on silica gel with methylene chloride and methanol.
There was obtained
1,6-bis-O-(4-methoxycarbonyl-phenyl)-3,4-O-methoxymethylene-2,5-O-methylen
e-D-mannitol, MS: m/z 504 ([M].sup.+).
C. 3.12 g of
1,6-bis-O-(4-methoxycarbonyl-phenyl)-3,4-O-methoxymethylene-2,5-O-methylen
e-D-mannitol were stirred at reflux for 6 hours in 100 ml of
methanol with 6 ml of sodium hydroxide solution (28%). After
cooling to 10.degree. C., the reaction mixture was adjusted to pH 2
with dilute hydrochloric acid and the methanol was then distilled
off in a water-jet vacuum. 100 ml of water were added to the
residue, the mixture was stirred in an ice bath for 1 hour, then
filtered and the residue was dried. There was thus obtained
1,6-bis-O-(4-carboxy-phenyl)-2,5-O-methylene-D-mannitol, MS: m/z
433 ([M-H].sup.-).
D. 2.05 g of
1,6-bis-O-(4-carboxy-phenyl)-2,5-O-methylene-D-mannitol were
stirred at reflux for 18 hours in 55 ml of 20% sulfuric acid in
methanol. Then, after cooling to room temperature, 50 ml of
ice-water were added and the methanol was distilled off in a
water-jet vacuum. The residual heterogeneous aqueous phase was
filtered and the residue was dried. There was obtained
1,6-bis-O-(4-methoxycarbonyl-phenyl)-D-mannitol, MS: m/z 449
([M-H].sup.-).
E. 2.33 g of 1,6-bis-O-(4-methoxycarbonyl-phenyl)-D-mannitol were
reacted and worked up in analogy to Example 34.C. There was
obtained 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS: m/z 421
([M-H].sup.-).
F. 2.10 g of 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were stirred
at room temperature for 20 hours in 30 ml of pyridine with 5.1 ml
of acetic anhydride. The reaction mixture was worked up
extractively with ice-water and methylene chloride. The organic
phase was dried over magnesium sulfate, filtered and concentrated.
The residue was recrystallized from methanol and methylene
chloride. There was obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS:
m/z 589 ([M-H].sup.-).
G. 1.18 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were
reacted with
1-O-(4-amino-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol in
analogy to Example 33.D. The crude product was chromatographed on
silica gel with methylene chloride and methanol. There was obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arab
init-1-yloxy)-phenylcarbamoyl]-phenyl]-D-mannitol, MS: m/z 1201
([M+H].sup.+).
H. 2.28 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arab
init-1-yloxy)-phenylcarbamoyl]-phenyl]-D-mannitol were stirred at
room temperature for 18 hours with 2.0 g of potassium carbonate in
60 ml of methanol with the addition of 10 ml of water. The methanol
was distilled off in a water-jet vacuum, 50 ml of water were added
to the residue and the mixture was filtered. After drying over
phosphorus pentoxide, there was obtained
1,6-O-bis-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenylcar
bamoyl]-phenyl]-D-mannitol, MS: m/z 1033 ([M+H].sup.+).
I. 1.67 g of
1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenylcar
bamoyl]-phenyl]-D-mannitol were dissolved in 50 ml of toluene,
treated with 15 ml of trifluoroacetic acid (70% in water) and
stirred at reflux for 3 hours. Subsequently, 50 ml of toluene were
added twice and the mixture was concentrated in a water-jet vacuum
each time. The thus-obtained residue was dried in a high vacuum at
room temperature over phosphorus pentoxide for 4 hours. There was
thus obtained
1,6-O-bis-[4-(4-D-arabinit-1-yloxy-phenylcarbamoyl)-phenyl]-D-mannitol,
IR: (KBr, cm.sup.-1): 3307, 1638, 1607, 1538, 1249, 1076, 826.
K. 1.31 g of
1,6-bis-O-[4-(4-D-arabinit-1-yloxy-phenyl-carbamoyl)-phenyl]-D-mannitol
were reacted with sulfur trioxide-trimethylamine complex in analogy
to Example 1.B. There was thus obtained
1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-phenylcarbamoyl
]-phenyl]-2,3,4,5-tetra-O-sulfo-D-mannitol dodecasodium salt, MS:
m/z 2097.0 (reconstructed M).
EXAMPLE 35
A. 10.01 g of meso-tartaric acid monohydrate were stirred at reflux
under argon for 15 minutes in 35 ml of acetic anhydride with the
addition of 0.3 ml of concentrated sulfuric acid; after cooling the
reaction mixture to 5.degree. C. 150 ml of diethyl ether were added
while stirring, the mixture was then filtered and the filtrate was
concentrated. There was thus obtained di-O-acetyl-meso-tartaric
anhydride, MS: m/z 235.2 ([M+H].sup.+) (=dicarboxylic acid), IR:
(KBr, cm.sup.-1): 1800, 1752, 1214.
B. 2.16 g of di-O-acetyl-meso-tartaric anhydride and 2.60 g of
1-O-(4-amino-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol were
stirred at room temperature for 16 hours in 120 ml of methylene
chloride. After distillation of the solvent, the product was
chromatographed on silica gel with methylene chloride and methanol.
There was obtained a mixture of (2R,3S)- and
(2S,3R)-di-O-acetyl-N-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-
phenyl]-meso-tartaramic acid, MS: m/z 538.4 ([M-H].sup.-).
C. 0.54 g of a mixture of (2R,3S)- and
(2S,3R)-di-O-acetyl-N-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-
phenyl]-meso-tartaramic acid in 15 ml of methylene chloride was
reacted at -20.degree. C. with 0.10 ml of oxalyl chloride with the
addition of 1 drop of dimethylformamide; after 2 hours firstly 0.28
ml of triethylamine and then 0.32 g of
1-O-(4-amino-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
dissolved in 5 ml of methylene chloride were added dropwise at
-25.degree. C. After warming to room temperature, the solvent was
distilled off and the residue was chromatographed on silica gel
with methylene chloride and methanol. There was obtained
di-O-acetyl-N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-p
henyl]-meso-tartaramide, MS: m/z 845.6 ([M+H].sup.+).
D. 2.32 g of
di-O-acetyl-N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-p
henyl]-meso-tartaramide were stirred at room temperature for 3
hours with 2.78 g of potassium carbonate in methanol/water in
analogy to Example 34.H. The reaction mixture was worked up
extractively with water and ethyl acetate. The crude product was
chromatographed on silica gel with methylene chloride and
acetonitrile. There was obtained
N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyl]-meso-
tartaramide, MS: m/z 761.3 ([M+H].sup.+).
E. 1.40 g of
N,N'-bis-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyl]-meso-
tartaramide were dissolved in 45 ml of dioxan, treated with 15 ml
of trifluoroacetic acid (70% in water) and stirred at reflux for 3
hours. Subsequently, 50 ml of toluene were added twice and the
mixture was concentrated in a water-jet vacuum each time. The
thus-obtained residue was dried in a high vacuum at at 50.degree.
C. over phosphorus pentoxide for 16 hours. There was obtained
N,N'-bis-(4-D-arabinit-1-yloxy-phenyl)-meso-tartaramide, IR: (KBr,
cm.sup.-1): 3390, 3304, 1661, 1604, 1539, 1513, 1241, 1077, 1042,
824.
F. 0.90 g of
N,N'-bis-(4-D-arabinit-1-yloxy-phenyl)-meso-tartaramide was reacted
with sulfur trioxide-trimethylamine complex in analogy to Example
1.B. There was thus obtained
di-O-sulfo-N,N'-bis-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-phenyl]-
meso-tartaramide decasodium salt, MS: m/z 1621.0 (reconstructed
M).
EXAMPLE 36
A. 14.6 g of 2,3:4,5-di-O-isopropylidene-D-arabinitol (European
Patent Application 247721 A1, 21st. Apr. 1987, DOW CHEMICAL
COMPANY) were reacted with 12.7 g of p-toluenesulfonyl chloride in
55 ml of pyridine with the addition of 0.05 g of
4-(N,N-dimethylamino)-pyridine. After distillation of the solvent,
the reaction mixture was worked up extractively with dilute
hydrochloric acid/ice and ethyl acetate. There was obtained
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
which was recrystallized from ethyl acetate/n-hexane, elementary
analysis calculated for C.sub.18 H.sub.26 O.sub.7 S: C=55.94%,
H=6.78%; found: C=56.02%, H=6.77%.
B. 11.60 g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
were reacted with 8.50 g of 4'-benzyloxy-biphenyl-biphenyl-4-ol (H.
Kapitza & R. Zentel, Makromol. Chem. 192, 1859 (1991)) and 20.7
g of potassium carbonate in 350 ml of N,N-dimethylformamide in
analogy to Example 33.A. After distillation of the solvent, the
crude product was chromatographed on silica gel with methylene
chloride and methanol. There was obtained
1-O-(4'-benzyloxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol,
MS: m/z 490 ([M].sup.+).
C. 9.80 g of
1-O-(4'-benzyloxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
were debenzylated by catalytic hydrogenation with 2.5 g of
Pd-charcoal (10%) in ethyl acetate. There was obtained
1-O-(4'-hydroxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol,
elementary analysis calculated for C.sub.23 H.sub.28 O.sub.6 :
C=68.98%, H=7.05%; found: C=68.76%, H=7.10%.
D. 2.00 g of
1-O-(4'-hydroxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
and 1.18 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol
were reacted and worked up as described in Example 33.A. The crude
product was chromatographed on silica gel with n-hexane, methylene
chloride and acetonitrile. There was obtained
1,4-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-2,3-O-isopropylidene-L-threitol, MS: m/z 927.4
([M+H].sup.+).
E. 1.63 g of
1,4-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-2,3-O-isopropylidene-L-threitol were dissolved in 50 ml of
dioxan, treated with 15 ml of trifluoroacetic acid (70% in water)
and stirred at reflux for 3 hours. After cooling to room
temperature, the mixture was concentrated and the residue was
treated twice with 50 ml of toluene and azeotropically distilled.
The thus-obtained residue was taken up in 50 ml of water, stirred
at room temperature for 1 hour, then cooled to 10.degree. C. and
filtered. After drying at 50.degree. C. over phosphorus pentoxide,
there was obtained
1,4-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-L-threitol,
elementary analysis calculated for C.sub.38 H.sub.46 O.sub.14 :
C=6.80%, H=6.38%; found: C=63.12%, H=6.21%.
F. 1.09 g of
1,4-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-L-threitol were
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
2,3-di-O-sulfo-1,4-bis-O-[4'-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-bi
phenyl-4-yl]-L-threitol decasodium salt, MS: m/z 1746.0
(reconstructed M).
EXAMPLE 37
A. 1.37 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
and 1.96 g of
1-O-(4'-hydroxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
(Example 36.C.) were reacted in analogy to Example 33.A. The crude
product was chromatographed on silica gel with n-hexane and
methylene chloride. There was obtained
1,6-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-2,3:4,5-di-O-isopropylidene-galactitol, MS: m/z 1026.5
([M].sup.+).
B. 1.70 g of
1,6-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-2,3:4,5-di-O-isopropylidene-galactitol were reacted with
trifluoroacetic acid (75%) in dioxan in analogy to Example 35.E.
and worked up analogously. There was obtained
1,4-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-galactitol,
elementary analysis calculated for C.sub.40 H.sub.50 O.sub.16 :
C=61.06%, H=6.41%; found: C=60.99%, H=6.50%.
C. 1.10 g of
1,4-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-galactitol were
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4'-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yl
oxy)-biphenyl-4-yl]-galactitol dodecasodium salt, MS: m/z 2011.0
(reconstructed M).
EXAMPLE 38
A. 1.96 g of
1-O-(4'-hydroxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
(Example 36.C.) and 0.56 g of
1,2:5,6-dianhydro-3,4-O-isopropylidene-D-mannitol (Y. Le Merrer et
al. Heterocyles 25, 541 (1987)) were stirred at 100.degree. C.
under argon for 6 hours in 130 ml of dimethylformamide with the
addition of 4.15 g of potassium carbonate. The reaction mixture was
poured on to ice-water, extracted with methylene chloride, the
combined methylene chloride phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The thus-obtained
crude product was chromatographed on silica gel with hexane and
ethyl acetate. There was thus obtained
1,6-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-3,4-O-isopropylidene-D-mannitol, MS: m/z 1010.6
([M+Na].sup.+).
B. 1.60 g of
1,6-bis-O-[4'-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-biphenyl-4-
yl]-3,4-O-isopropylidene-D-mannitol were reacted with
trifluoroacetic acid (50%) in dioxan in analogy to Example 35.E.
There was obtained
1,6-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-D-mannitol, IR:
(KBr, cm.sup.-1): 3381, 1607, 1499, 1242, 1176, 1045, 823.
C. 1.18 g of
1,6-bis-O-(4'-D-arabinit-1-yloxy-biphenyl-4-yl)-D-mannitol were
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4'-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yl
oxy)-biphenyl-4-yl]-D-mannitol dodecasodium salt, MS: m/z 2011.0
(reconstructed M).
EXAMPLE 39
A. 30.1 g of anisole and 26.0 g of 1,1-dichloro-2,2-diethoxy-ethane
were reacted at 5.degree. C. under argon with the addition of 42 ml
of concentrated sulfuric acid. The reaction mixture was poured on
to 350 ml of ice-water and thereafter suction filtered; the crystal
slurry was washed with water and dried. The thus-obtained crude
product was recrystallized from methylene chloride and n-hexane.
There was thus obtained
4,4'-dimethoxy-1,1'-(2,2-dichloro-ethylidene)-dibenzene, m.p.:
113.degree.-160.degree. C.
B. 6.0 g of 4,4'-dimethoxy-1,1'-(2,2-dichloro-ethylidene)-dibenzene
were heated at 190.degree. C. with 9.7 g of potassium
tert.-butylate. After the addition of ice-water, the mixture was
filtered and the residue was washed with water and recrystallized
from methylene chloride and n-hexane. There was obtained
4,4'-dimethoxy-1,1'-ethyndiyl-dibenzene, m.p.:
140.degree.-142.degree. C.
C. 16.4 g of 4,4'-dimethoxy-1,1'-ethyndiyl-dibenzene in 240 ml of
methylene chloride were reacted with 12.6 ml of boron tribromide at
-75.degree. C. under argon. After hydrolysis, the product was
isolated by extraction with ether. The organic phase was dried over
magnesium sulfate, filtered and concentrated. The crude product was
chromatographed on silica gel with n-hexane and ethyl acetate.
There was thus obtained 4,4'-ethyndiyl-diphenol, MS: m/z 210.0
([M].sup.+).
D. 2.56 g of 4,4'-ethyndiyl-diphenol and 4.71 g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were reacted at 60.degree. C. for 70 hours in 500
ml of dimethylformamide with the addition of 8.43 g of potassium
carbonate. The reaction mixture was subsequently poured on to
ice-water, extracted with methylene chloride, the combined
methylene chloride phases were washed with water, dried over
magnesium sulfate, filtered and concentrated. The thus-obtained
crude product was chromatographed on silica gel with methylene
chloride and acetonitrile. There was obtained
1-O-[4-(4-hydroxy-phenylethynyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-ara
binitol, MS: m/z 424.0 ([M].sup.+).
E. 2.12 g of
1-O-[4-(4-hydroxy-phenylethynyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-ara
binitol and 1.43 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
were reacted in analogy to Example 33.A. with the addition of 1.73
g of potassium carbonate and worked up. The crude product was
chromatographed on silica gel with n-hexane and methylene chloride.
There was obtained
1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyleth
ynyl]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol, IR: (KBr,
cm.sup.-1): 2230, 1608, 1516, 1246, 1173, 1064, 1025, 836.
F. 1.80 g of
1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-phenyleth
ynyl]-phenyl]-2,3:4,5-di-O-isopropyl-idene-galactitol were reacted
at reflux for 7 hours in analogy to Example 35.E. and subsequently
worked up analogously. There was obtained
1,6-bis-O-[4-(4-D-arabinit-1-yloxy-phenylethynyl)-phenyl]-galactitol,
which was used directly in the next step.
G. 1.40 g of
1,6-bis-O-[4-(4-D-arabinit-1-yloxy-phenylethynyl)-phenyl]-galactitol
were reacted with sulfur trioxide-trimethylamine complex in analogy
to Example 1.B. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
yloxy)-phenyl-ethynyl]-phenyl]-galactitol dodecasodium salt, MS:
m/z 2060.0 (reconstructed M).
EXAMPLE 40
A. 9.61 g of 2,3-dihydroxy-naphthalene were dissolved in 70 ml of
0.95M sodium methylate solution in methanol, treated with 6.92 ml
of benzyl chloride and stirred at reflux for 4 hours. After cooling
to room temperature, the mixture was worked up extractively with
water, dilute hydrochloric acid and methylene chloride. The crude
product was chromatographed on silica gel with n-hexane and
methylene chloride. There was thus obtained
3-benzyloxy-naphthalen-2-ol, MS: m/z 250.0 ([M].sup.+).
B. 2.80 g of 3-benzyloxy-naphthalen-2-ol and 4.33 g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were reacted at 100.degree. C. for 6 hours in
analogy to Example 33.A. and worked up analogously. The
thus-obtained crude product was chromatographed on silica gel with
methylene chloride. The product was recrystallized from n-hexane.
There was obtained
1-O-(3-benzyloxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
, MS: m/z 464.0 ([M].sup.+).
C. 4.80 g of
1-O-(3-benzyloxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
were hydrogenated in methanol at room temperature and normal
pressure for 5 hours using 1.0 g of Pd charcoal (10%) as the
catalyst. After filtration of the catalyst, the solvent was
distilled off in a water-jet vacuum and the residue was
chromatographed on silica gel with methylene chloride and methanol.
There was obtained
1-O-(3-hydroxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol,
MS: m/z 374.0 ([M].sup.+).
D. 1.10 g of
1-O-(3-hydroxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
and 0.84 g of
2,3:4,5-di-O-isopropyl-idene-1.6-bis-O-(4-methyl-phenylsulfonyl)-galactito
l were reacted at 100.degree. C. for 6 hours in analogy to Example
33.A. and worked up analogously. The crude product was
chromatographed on silica gel with n-hexane and ethyl acetate.
There was thus obtained
1,6-bis-O-[3-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-naphthalen-2
-yl]-2,3:4,5-di-O-isopropylidene-galactitol, IR: (film, cm.sup.-1):
1628, 1510, 1256, 1216, 1176, .1096, 1017, 747.
E. 0.90 g of
1,6-bis-O-[3-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-naphthalen-2
-yl]-2,3:4,5-di-O-isopropylidene-galactitol was reacted with 10 ml
of trifluoroacetic acid (70% in water) in 25 ml of dioxan in
analogy to Example 35.E. After working up, there was obtained
1,6-bis-O-(3-D-arabinit-1-yloxy-naphthalen-2-yl)-galactitol which
was used directly in the next step.
F. 0.83 g of
1,6-bis-O-(3-D-arabinit-1-yloxy-naphthalen-2-yl)-galactitol was
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
1,6-bis-O-[3-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-naphthalen-2-yl]-2
,3,4,5-tetra-O-sulfo-galactitol dodecasodium salt, MS: m/z 1960.0
(reconstructed M).
EXAMPLE 41
A. 1.53 g of
1-O-(3-hydroxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
(Example 40.C.) and 0.97 g of
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenylsulfonyl)-L-threitol
were stirred at 100.degree. C. for 21 hours analogously to Example
33.A. and worked up analogously. The crude product was
chromatographed on silica gel with toluene and ethyl acetate. There
was thus obtained
1,4-bis-O-[3-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-naphthalen-2
-yl]-2,3-O-isopropylidene-L-threitol which was used directly in the
next step.
B. 0.65 g of
1,4-bis-O-[3-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-naphthalen-2
-yl]-2,3-O-isopropylidene-L-threitol was stirred at reflux for 7
hours in analogy to Example 35.E. and worked up analogously. There
was obtained
1,4-bis-O-(3-D-arabinit-1-yloxy-naphthalen-2-yl)-L-threitol which
was used directly in the next step.
C. 0.50 g of
1,4-bis-O-(3-D-arabinit-1-yloxy-naphthalen-2-yl)-L-threitol was
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
2,3-di-O-sulfo-1,4-bis-O-[3-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-yloxy)-nap
hthalen-2-yl]-L-threitol decasodium salt, MS: m/z 1695.0
(reconstructed M).
EXAMPLE 42
0.50 g of
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
yloxy)-phenylethynyl]-phenyl]-galactitol dodecasodium salt (Example
39.G.) was hydrogenated at normal pressure using 0.35 g of
palladium on charcoal (105) in 5 ml of water. After filtration of
the catalyst, the filtrate was lyophilized. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[2-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit
-1-yloxy)-phenyl]-ethyl]-phenyl]-galactitol dodecasodium salt, MS:
m/z 2067.0 (reconstructed M).
EXAMPLE 43
A. 30.00 g of bis-(4-hydroxy-phenyl)-methane were dissolved in 240
ml of 0.82M sodium ethylate solution in ethanol, treated with 19.80
ml of benzyl bromide and stirred at reflux for 4 hours. After
cooling to room temperature, the mixture was worked up extractively
with ice-water, dilute hydrochoric acid and methylene chloride. The
thus-obtained crude product was chromatographed on silica gel with
methylene chloride and ether. There was thus obtained
4-(4-benzyloxy-benzyl)-phenol, MS: m/z 290.0 ([M].sup.+).
B. 2.98 g of 1,2:5,6-dianhydro-3,4-O-isopropylidene-D-mannitol and
9.30 g of 4-(4-benzyloxy-benzyl)-phenol were stirred at for
100.degree. C. for 17 hours in analogy to Example 33.A. and worked
up analogously. The crude product was chromatographed on silica gel
with n-hexane and ethyl acetate. The pure product was
recrystallized from ethyl acetate and n-hexane. There was thus
obtained
1,6-bis-O-[4-(4-benzyloxy-benzyl)-phenyl]-3,4-O-isopropylidene-D-mannitol,
MS: m/z 784.4 ([M+NH.sub.4 ].sup.+).
C. 6.07 g of
1,6-bis-O-[4-(4-benzyloxy-benzyl)-phenyl]-3,4-O-isopropylidene-D-mannitol
were hydrogenated in 250 ml of ethyl acetate at normal pressure and
room temperature with the addition of 2.0 g of palladium on
charcoal (5%). After filtration of the catalyst, the solvent was
distilled off in a water-jet vacuum and the residue was
chromatographed on silica gel with methylene chloride and methanol.
There was obtained
1,6-bis-O-[4-(4-hydroxy-benzyl)-phenyl]-3,4-O-isopropylidene-D-mannitol,
MS: m/z 604.4 ([M+NH.sub.4 ].sup.+).
D. 1.20 g of
1,6-bis-O-[4-(4-hydroxy-benzyl)-phenyl]-3,4-O-isopropylidene-D-mannitol
and 1.58 g
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were stirred at 100.degree. C. for 21 hours
analogously to Example 33.A. and worked up analogously. The crude
product was chromatographed on silica gel with methylene chloride
and methanol. There was thus obtained
1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-benzyl]-p
henyl]-3,4-O-isopropylidene-D-mannitol, MS: m/z 1032.5 ([M+NH.sub.4
].sup.+).
E. 1.30 g of
1,6-bis-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-benzyl]-p
henyl]-3,4-O-isopropylidene-D-mannitol were stirred at reflux for 3
hours analogously to Example 35.E. After cooling to room
temperature, the separated crystals were filtered off under suction
and dried in a high vacuum at 50.degree. C. over phosphorus
pentoxide. There was obtained
1,6-bis-O-[4-(4-D-arabinit-1-yloxy-benzyl)-phenyl]-D-mannitol, MS:
m/z 832.4 ([M+NH.sub.4 ].sup.+).
F. 0.81 g of
1,6-bis-O-[4-(4-D-arabinit-1-yloxy-benzyl)-phenyl]-D-mannitol was
reacted with sulfur trioxide-trimethylamine complex in analogy to
Example 1.B. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
yloxy)-benzyl]-phenyl]-D-mannitol dodecasodium salt, MS: m/z 2039.0
(reconstructed M).
EXAMPLE 44
A. 3.65 g of methyl 4-hydroxy-benzoate and 7.73 g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were reacted at 100.degree. C. for 3 hours in 300
ml of dimethylformamide with the addition of 13.82 g of potassium
carbonate analogously to Example 33.A. and worked up. The crude
product was chromatographed on silica gel with methylene chloride
and methanol. There was thus obtained
2,3:4,5-di-O-isopropylidene-1-O-(4-methoxycarbonyl-phenyl)-D-arabinitol,
MS: m/z 366.0 ([M].sup.+).
B. 7.37 g of
2,3:4,5-Di-O-isopropylidene-1-O-(4-methoxycarbonyl-phenyl)-D-arabinitol
were stirred at 50.degree. C. for 16 hours with 20 ml of sodium
hydroxide solution (28%) in 300 ml of methanol. After
neutralization with 6N hydrochloric acid, the methanol was
distilled off in a water-jet vacuum. The residue was poured on to
ice-water, extracted with methylene chloride and the combined
methylene chloride phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The crude product was
chromatographed on silica gel with methylene chloride and methanol.
There was thus obtained
1-O-(4-carboxy-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol,
MS: m/z 352.0 ([M].sup.+).
C. 17.60 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
and 16.00 g of sodium azide were stirred at 100.degree. C. for 1
hour in 300 ml of dimethylformamide. The reaction mixture was
subsequently worked up extractively with ice-water and ethyl
acetate. The thus-obtained crude product was recrystallized from
methylene chloride and n-hexane. There was thus obtained
1,6-diazido-1,6-didesoxy-2,3:4,5-di-O-isopropylidene-galactitol,
MS: m/z 297.0 ([M-CH.sub.3 ].sup.+).
D. 9.20 g of
1,6-diazido-1,6-didesoxy-2,3:4,5-di-O-isopropylidene-galactitol
were hydrogenated in 250 ml of methanol at room temperature and
normal pressure with the addition of 2.50 g of palladium-charcoal
(10%). After filtration of the catalyst, the solvent was distilled
off in a water-jet vacuum. The residue was taken up in ethanol. Two
equivalents of hydrochloric acid (in ethanol) were added, the
mixture was again concentrated and the product was recrystallized
from methanol and ether. There was thus obtained
1,6-diamino-1,6-didesoxy-2,3:4,5-di-O-isopropylidene-galactitol
dihydrochloride, MS: m/z 245.0 ([M-CH.sub.3 ].sup.+).
E. 1.41 g of
1-O-(4-carboxy-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol and
0.70 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were stirred at
0.degree.-5.degree. C. in 40 ml of acetonitrile/dimethylformamide
(3:1) for 2 hours with the addition of 0.88 ml of
4-methyl-morpholine. Subsequently, 0.67 g of
1,6-diamino-1,6-didesoxy-2,3:4,5-di-O-isopropylidene-galactitol
dihydrochloride was added and the mixture was stirred at room
temperature for a further 18 hours. The reaction mixture was worked
up extractively with ice-water and methylene chloride. The crude
product was chromatographed on silica gel with methylene chloride
and methanol. By recrystallization from methylene chloride and
n-hexane there was obtained
1,6-didesoxy-2,3:4,5-di-O-isopropylidene-1,6-bis-[4-(2,3:4,5-di-O-isopropy
lidene-D-arabinit-1-yloxy)-benzoylamino]-galactitol, MS: m/z 929.3
([M+H].sup.+).
F. 1.32 g of
1,6-didesoxy-2,3:4,5-di-O-isopropylidene-1,6-bis-[4-(2,3:4,5-di-O-isopropy
lidene-D-arabinit-1-yloxy)-benzoylamino]-galactitol were stirred in
21 ml of glacial acetic acid/water 2:1 at 100.degree. C. for 4
hours. After cooling to room temperature, 30 ml of water were added
and the mixture was filtered. The product was washed twice with 5
ml of water each time and then dried at 50.degree. C. over
phosphorus pentoxide in a high vacuum for 3 hours. There was thus
obtained
1,6-bis-(4-D-arabinit-1-yloxy-benzoylamino)-1,6-didesoxy-galactitol,
MS: m/z 711.6 ([M+Na].sup.+).
G. 0.90 g of
1,6-bis-(4-D-arabinit-1-yloxy-benzoylamino)-1,6-didesoxy-galactitol
was reacted with sulfur trioxide-trimethylamine complex in analogy
to Example 1.B. There was thus obtained
1,6-didesoxy-2,3,4,5-tetra-O-sulfo-1,6-bis-[4-(2,3,4,5-tetra-O-sulfo-D-ara
binit-1-yloxy)-benzoylamino)-galactitol dodecasodium salt, MS: m/z
1912.0 (reconstructed M).
EXAMPLE 45
A. 4.85 g of methyl 3-hydroxy-2-naphthalene-2-carboxylate and 7.73
g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were reacted in 300 ml of dimethylformamide at
100.degree. C. for 4 hours with the addition of 13.82 g of
potassium carbonate analogously to Example 33.A. and worked up .
The crude product was chromatographed on silica gel with methylene
chloride and methanol. There was thus obtained
2,3:4,5-di-O-isopropylidene-1-O-(3-methoxycarbonyl-naphthalen-2-yl)-D-arab
initol, MS: m/z 416.0 ([M].sup.+).
B. 6.00 g of
2,3:4,5-di-O-isopropylidene-1-O-(3-methoxycarbonyl-naphthalen-2-yl)-D-arab
initol were stirred at room temperature for 16 hours with 14.4 ml
of sodium hydroxide solution (28%) in 250 ml of methanol. After
neutralization with 6N hydrochloric acid, the methanol was
distilled off in a water-jet vacuum. The residue was poured on to
ice-water, extracted with methylene chloride, the combined
methylene chloride phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The crude product was
chromatographed on silica gel with methylene chloride and methanol.
There was thus obtained
1-O-(3-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol,
MS: m/z 402.0 ([M].sup.+).
C. 1.61 g of
1-O-(3-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-D-arabinitol
and 0.70 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were reacted
with 0.67 g of
1,6-diamino-1,6-didesoxy-2,3:4,5-di-O-isopropylidene-galactitol
dihydrochloride with the addition of 0.88 ml of 4-methyl-morpholine
analogously to Example 44.E. and worked up. The crude product was
chromatographed on silica gel with methylene chloride and methanol.
There was thus obtained
1,6-didesoxy-2,3:4,5-di-O-isopropylidene-1,6-bis-[3-(2,3:4,5-di-O-isopropy
lidene-D-arabinit-1-yloxy)-naphthalen-2-ylcarbonylamino]-galactitol,
MS: m/z 1028.8 ([M].sup.+).
D. 1.95 g of
1,6-didesoxy-2,3:4,5-di-O-isopropylidene-1,6-bis-[3-(2,3:4,5-di-O-isopropy
lidene-D-arabinit-1-yloxy)-naphthalen-2-ylcarbonylamino]-galactitol
were reacted and worked up analogously to Example 44.F. There was
obtained
1,6-bis-(3-D-arabinit-1-yloxy-naphthalen-2-ylcarbonylamino)-1,6-didesoxy-g
alactitol, MS: m/z 788.8 ([M].sup.+).
E. 1.11 g of
1,6-bis-(3-D-arabinit-1-yloxy-naphthalen-2-ylcarbonylamino)-1,6-didesoxy-g
alactitol were reacted with sulfur trioxide-trimethylamine complex
in analogy to Example 1.b. There was thus obtained
1,6-didesoxy-2,3,4,5-tetra-O-sulfo-1,6-bis-[3-(2,3,4,5-tetra-O-sulfo-D-ara
binit-1-yloxy)-naphthalen-2-ylcarbonylamino]-galactitol
dodecasodium salt, MS: m/z 2013.0 (reconstructed M).
EXAMPLE 46
A. 27.75 g of 3,4-di-O-isopropylidene-D-mannitol and 65.25 g of
dibutyltin oxide were stirred at reflux for 2 hours in 2.5 l of
benzene using a water separator. Thereupon, the mixture was
concentrated in a water-jet vacuum to a total volume of 700 ml.
Subsequently, 46.25 g of tetrabutylammonium iodide were added at
room temperature, 37.50 ml of 3-bromo-propyn-1-yne were added
dropwise and the reaction mixture was stirred at 70.degree. C. for
7 hours. After concentration in a water-jet vacuum, the crude
product was chromatographed on silica gel with n-hexane and ethyl
acetate. There was thus obtained
1,6-di-O-prop-2-ynyl-3,4-O-isopropylidene-D-mannitol, MS: m/z 298.0
([M].sup.+).
B. 21.20 g of 1,6-di-O-prop-2-ynyl-3,4-O-isopropylidene-D-mannitol
were stirred at 100.degree. C. for 3 hours in 300 ml of glacial
acetic acid/water 2:1. The reaction mixture was concentrated in a
water-jet vacuum. 50 ml of toluene were added twice and the water
was distilled off azeotropically each time. The residue was dried
in a high vacuum over phosphorus pentoxide for 18 hours. There was
thus obtained 1,6-bis-O-prop-2-ynyl-D-mannitol which was used
directly in the next step.
C. 27.00 g of 1,6-bis-O-prop-2-ynyl-D-mannitol were dissolved in
300 ml of pyridine, treated at room temperature under argon with
100 ml of acetic anhydride and stirred for 4 hours. Subsequently,
the mixture was worked up extractively with water and ethyl
acetate. The thus-obtained crude product was chromatographed on
silica gel with methylene chloride and methanol. There was thus
obtained 2,3,4,5-tetra-O-acetyl-1,6-bis-O-prop-2-ynyl-D-mannitol,
MS: m/z 367.0 ([M-OAc].sup.+).
D. 9.80 g of 4-iodo-phenol and 15.80 g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenylsulfonyl)-D-arabinitol
(Example 36.A.) were reacted at 100.degree. C. for 6 hours in 500
ml of dimethylformamide with the addition of 56.00 g of potassium
carbonate and worked up analogously to Example 33.A. The crude
product was chromatographed on silica gel with hexane and ethyl
acetate. There was thus obtained
1-O-(4-iodophenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol, MS:
m/z 434.0 ([M].sup.+).
E. 14.90 g of
1-O-(4-iodo-phenyl)-2,3:4,5-di-O-isopropylidene-D-arabinitol were
reacted and worked up analogously to Example 46.B. The crude
product was suspended in ether, filtered and dried over phosphorus
pentoxide in a high vacuum at 50.degree. C. for 16 hours. The
thus-obtained 1-O-(4-iodo-phenyl)-D-arabinitol was used directly in
the next step.
F. 12.85 g of 1-O-(4-iodo-phenyl)-D-arabinitol were reacted and
worked up analogously to Example 46.C. The crude product was
recrystallized from ethyl acetate and hexane. There was thus
obtained 2,3,4,5-tetra-O-acetyl-1-O-(4-iodo-phenyl)-D-arabinitol,
MS: m/z 522.0 ([M].sup.+).
G. 2.61 g of
2,3,4,5-tetra-O-acetyl-1-O-(4-iodo-phenyl)-D-arabinitol, 0.58 g of
palladium(O)-tetrakis-triphenylphosphine and 0.19 g of copper(I)
iodide were stirred at room temperature under argon in 25 ml of
diisopropylamine/dimethylformamide (1:1) for 45 minutes.
Subsequently, a solution of 1.07 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-prop-2-ynyl-D-mannitol in 10 ml of
diisopropylamine/dimethylformamide (1:1) was added dropwise and the
reaction mixture was stirred at room temperature for 70 hours. The
mixture was thereupon concentrated with the addition of 100 ml of
toluene and the dimethylformamide was then distilled off in a high
vacuum. The thus-obtained crude product was chromatographed on
silica gel with methylene chloride and methanol. There was thus
obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[4-(2,3,4,5-tetra-O-acetyl-D-arabinit-
1-yloxy)-phenyl]-prop-2-ynyl]-D-mannitol which was used directly in
the next step.
H. 3.42 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[4-(2,3,4,5-tetra-O-acetyl-D-arabinit-
1-yloxy)-phenyl]-prop-2-ynyl]-D-mannitol were dissolved in 100 ml
of methanol, treated with 10 ml of sodium methylate solution (5.4
molar) and stirred at room temperature for 16 hours. The reaction
solution was adjusted to pH 2-3 with aqueous hydrochloric acid and
concentrated. The residue was suspended in water and filtered, and
the residue was washed twice with 10 ml of water each time and
dried over phosphorus pentoxide in a high vacuum for 5 hours. There
was thus obtained
1,6-bis-O-[3-(4-D-arabinit-1-yloxy-phenyl)-prop-2-ynyl]-D-mannitol,
MS: m/z 733.6 ([M+Na].sup.+).
I. 1.70 g of
1,6-bis-O-[3-(4-D-arabinit-1-yloxy-phenyl)-prop-2-ynyl]-D-mannitol
were reacted with sulfur trioxide-trimethylamine complex in analogy
to Example 1.B. There was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[3-[4-(2,3,4,5-tetra-O-sulfo-D-arabinit-1-
yloxy)-phenyl]-prop-2-ynyl]-D-mannitol dodecasodium salt, MS: m/z
1934.0 (reconstructed M).
EXAMPLE 47
A. 14.10 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol
and 6.00 g of 4-benzyloxy-phenol were dissolved in 300 ml of
dimethylformamide, treated with 20.70 g of potassium carbonate and
stirred at 100.degree. C. for 6 hours. The reaction mixture was
worked up extractively with ice-water and methylene chloride. The
crude product was subsequently chromatographed on silica gel with
n-hexane and methylene chloride. There was thus obtained
1-O-(4-benzyloxy-phenyl)-2,3-O-isopropylidene-4-O-(4-methyl-phenylsulfonyl
)-L-threitol, MS: m/z 498.0 ([M].sup.+).
B. 5.81 g of 4-(4-benzyloxy-benzyl)-phenol (Example 43.A.) and 7.73
g of
2,3:4,5-di-O-isopropylidene-1-O-(4-methyl-phenyl-sulfonyl)-D-arabinitol
were reacted at 100.degree. C. in dimethylformamide analogously to
Example 47.A. and worked up analogously. The crude product was
chromatographed on silica gel with n-hexane and methylene chloride.
There was thus obtained
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-arabinit
ol, MS: m/z 504.0 ([M].sup.+).
C. 8.30 g of
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-arabinit
ol were hydrogenated in 85 ml of tetrahydrofuran at normal pressure
and room temperature with the addition of 1.60 g of palladium on
charcoal (10%). After filtration of the catalyst, the filtrate was
concentrated. There was thus obtained
1-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-arabinitol
, MS: m/z 414.0 ([M].sup.+).
D. 1.66 g of
1-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3:4,5-di-O-isopropylidene-D-arabinitol
and 1.99 g of
1-O-(4-benzyloxy-phenyl)-2,3-O-isopropylidene-4-O-(4-methyl-phenylsulfonyl
)-L-threitol were reacted at 100.degree. C. in dimethylformamide
analogously to Example 47.A. and worked up analogously. The crude
product was chromatographed on silica gel with n-hexane and
methylene chloride. There was thus obtained
1-O-(4-benzyloxy-phenyl)-4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit
-1-yloxy)-benzyl]-phenyl]-L-threitol, MS: m/z 740.0
([M].sup.+).
E. 2.50 g of
1-O-(4-benzyloxy-phenyl)-4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit
-1-yloxy)-benzyl]-phenyl]-L-threitol were hydrogenated and worked
up analogously to Example 47.C. There was thus obtained
1-O-(4-hydroxy-phenyl)-4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1
-yloxy)-benzyl]-phenyl]-L-threitol, MS: m/z 650.0 ([M].sup.+).
F. 1.80 g of
1-O-(4-hydroxy-phenyl)-4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1
-yloxy)-benzyl]-phenyl]-L-threitol and 0.79 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
were reacted at reflux in 20 ml of dimethylformamide for 3 hours in
analogy to Example 47.A. and worked up analogously. The crude
product was chromatographed on silica gel with toluene and ethyl
acetate. There was obtained
1,6-bis-O-[4-[4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-b
enzyl]-phenyl]-2,3-di-O-isopropylidene-L-threit-1-yloxy]-phenyl]-2,3:4,5-di
-O-isopropylidene-galactitol which was used directly in the next
step.
G. 0.35 g of
1,6-bis-O-[4-[4-O-[4-[4-(2,3:4,5-di-O-isopropylidene-D-arabinit-1-yloxy)-b
enzyl]-phenyl]-2,3-di-O-isopropyldene-L-threit-1-yloxy]-phenyl]-2,3:4,5-di-
O-isopropylidene-galactitol was stirred at reflux for 3 hours in
analogy to Example 35.E. and worked up analogously. There was thus
obtained
1,6-bis-O-[4-[4-O-[4-[4-(D-arabinit-1-yloxy)-benzyl]-phenyl]-L-threit-1-yl
oxy]-phenyl]-galactitol which was used directly in the next
step.
H. 0.27 g of
1,6-bis-O-[4-[4-O-[4-[4-(D-arabinit-1-yloxy)-benzyl]-phenyl]-L-threit-1-yl
oxy]-phenyl]-galactitol was reacted with sulfur
trioxide-trimethylamine complex in analogy to Example 1.B. There
was thus obtained
2,3,4,5-tetra-O-sulfo-1,6-bis-O-[4-[4-O-[4-[4-(2,3,4,5-tetra-O-sulfo-D-ara
binit-1-yloxy)-benzyl]-phenyl]-2,3-di-O-sulfo-L-threit-1-yloxy]-phenyl]-gal
actitol hexadecasodium salt, MS: m/z 2840.0 (reconstructed M).
EXAMPLE 48
A. 5.0 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
, 5.26 g of 4-benzyloxy-phenol and 3.6 g of finely ground anhydrous
potassium carbonate were suspended in 60 ml of dimethylformamide
and stirred at 130.degree. C. under argon for 18 hours.
Subsequently, the reaction mixture was diluted with water and the
thus-formed crystals were filtered off. There was obtained
1,6-bis-O-(4-benzyloxy-phenyl)-2,3:4,5-di-O-isopropylidene-galactitol
in the form of colorless crystals, MS: m/z 625 ([M-H].sup.+).
B. 4.0 g of
1,6-bis-O-(4-benzyloxy-phenyl)-2,3:4,5-di-O-isopropylidene-galactitol
were exhaustively hydrogenated in 150 ml of tetrahydrofuran in a
hydrogen atmosphere with the addition of 0.5 g of palladium on
charcoal (10%). Subsequently, the reaction mixture was filtered
over a 0.8.mu. cellulose filter. The filtrate was concentrated and
the residue was crystallized from ether; there was thus obtained
1,6-bis-O-(4-hydroxy-phenyl)-2,3:4,5-di-O-isopropylidene-galactitol
as a colorless solid, MS: m/z 446 ([M].sup.+).
C. 1.78 g of
1,6-bis-O-(4-hydroxy-phenyl)-2,3:4,5-di-O-isopropylidene-galactitol,
3.2 g of
1-O-benzyl-2,3-O-isopropylidene-4-O-(4-methyl-phenylsulfonyl)-D-threitol
( E. Hungerbuhler & D. Seebach, Helvetica Chimica Acta 64, 687
(1981)) and 1.2 g of finely ground anhydrous potassium carbonate
were suspended in 25 ml of dimethylformamide and stirred at
130.degree. C. under argon for 24 hours. The reaction mixture was
subsequently diluted with water and the aqueous phase was extracted
with ether. The combined ether phases were dried over magnesium
sulfate and concentrated. The thus-obtained crude product was
chromatographed on silica gel with 5% ether in methylene chloride.
There was thus obtained
1,6-bis-O-[4-(4-O-benzyl-2,3-O-isopropylidene-D-threit-1-yloxy)-phenyl]-2,
3:4,5-di-O-isopropylidene-galactitol in the form of colorless
crystals, MS: m/z 932.6 ([M+NH.sub.4 ].sup.+).
D. 2.3 g of
1,6-bis-O-[4-(4-O-benzyl-2,3-O-isopropylidene-D-threit-1-yloxy)-phenyl]-2,
3:4,5-di-O-isopropylidene-galactitol were exhaustively hydrogenated
in 20 ml of tetrahydrofuran in a hydrogen atmosphere with the
addition of 0.2 g of palladium on charcoal (10%). Subsequently, the
reaction mixture was filtered over a 0.8.mu. cellulose filter and
concentrated; there was thus obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-(2,3-O-isopropylidene-D-threit-1-
yloxy)-phenyl]-galactitol as a colorless oil, MS: m/z 734
([M].sup.+).
E. 1.74 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-(2,3-O-isopropylidene-D-threit-1-
yloxy)-phenyl]-galactitol dissolved in 15 ml of pyridine were
treated at 0.degree. C. with a solution of 1.35 g of
p-toluenesulfonyl chloride in 5 ml of pyridine and stirred at room
temperature for 60 hrs. Thereupon, the reaction mixture was treated
with ice-water, stirred at room temperature for 1.5 hours and
extracted with ether. The combined ether phases were washed with 1N
hydrochloric acid and water, dried over magnesium sulfate and
concentrated. The thus-obtained crude product was chromatographed
on silica gel with 5% ether in methylene chloride. There was thus
obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-(4-meth
yl-phenyl-sulfonyl)-D-threit-1-yloxy]-phenyl]-galactitol as a
colorless oil, MS: m/z 870 ([M-TosOH].sup.+).
F. 2.21 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-(4-meth
yl-phenyl-sulfonyl)-D-threit-1-yloxy]-phenyl]-galactitol, 1.13 g of
methyl (E)-3-(4-hydroxy-phenyl)-acrylate and 0.87 g of finely
ground anhydrous potassium carbonate were suspended in 10 ml of
dimethyl-formamide and stirred at 130.degree. C. under argon for 20
hours. Subsequently, the reaction mixture was concentrated, diluted
with water and extracted with methylene chloride. The combined
methylene chloride phases were washed with 1N sodium hydroxide
solution and water, dried over magnesium sulfate and concentrated.
The thus-obtained crude product,
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-[4-[(E)
-2-methoxycarbonyl-vinyl]-phenyl]-D-threit-1-yloxy]-phenyl]-galactitol,
was thereupon dissolved in 30 ml of methanol, treated with 3 ml of
concentrated sodium hydroxide solution and 3 ml of water and heated
under reflux for 3 hours. Thereupon, the mixture was acidified with
1N hydrochloric acid while cooling with ice and the thus-obtained
precipitate was filtered off. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3-O-isopropylidene-D-
threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol in
form of colorless crystals, MS: m/z 1025.4 ([M-H].sup.-).
G. 1.02 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3-O-isopropylidene-D-
threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol
dissolved in 5 ml of dimethylformamide were treated with 0.3 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.40 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.40 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with water and the mixture
was boiled briefly and filtered. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3-O-is
o-propylidene-D-threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galacti
tol as a brownish solid, MS: m/z 1353.6 ([M+H].sup.+).
H. 0.20 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-2,3-O-is
opropylidene-D-threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactit
ol was suspended in 3 ml of dioxan, 0.5 ml of trifluoroacetic acid
and 0.7 ml of water and heated under reflux at 95.degree. C. for 18
hours. Subsequently, the reaction mixture was concentrated to
dryness; there was thus obtained
1,6-bis-O-[4-[4-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-D-threit
-1-yloxy]-phenyl]-galactitol as a colorless solid, MS: m/z 1215.9
([M+Na].sup.+).
I. The
1,6-bis-O-[4-[4-O-[4-[(E)-2-D-glucit-1-ylcarbamoyl-vinyl]-phenyl]-D-threit
-1-yloxy]-phenyl]-galactitol obtained above was converted
analogously to Example 1.B. into
1,6-bis-O-[4-[4-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoy
l)-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-
sulfo-galactitol octadecasodium salt, [a]-3.6.degree. (c 0.7;
water).
EXAMPLE 49
A. 0.15 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoy
l)-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-
sulfo-galactitol octadecasodium salt in 5 ml of distilled water was
exhaustively hydrogenated in a hydrogen atmosphere with the
addition of 100 mg of palladium on charcoal (10%). Subsequently,
the reaction mixture was filtered over a 0.8.mu. cellulose filter
and the filtrate was lyophilized; there was thus obtained
1,6-bis-O-[4-[4-O-[4-[2-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-e
thyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-sulf
o-galactitol octadecasodium salt, [a]-3.4.degree. (c 0.5;
water).
EXAMPLE 50
A. 37.6 g of
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenyl-sulfonyl)-L-threitol,
16.0 g of methyl 3-hydroxy-naphthalene-2-carboxylate and 13 g of
finely ground anhydrous potassium carbonate were suspended in 300
ml of acetonitrile and stirred at 100.degree. C. under argon for 60
hours. Subsequently, the reaction mixture was diluted with water
and the aqueous phase was extracted with ether. The combined ether
phases were dried over magnesium sulfate and concentrated. The
thus-obtained crude product was chromatographed on silica gel with
ether in methylene chloride. There was thus obtained crude
2,3-O-isopropylidene-1-O-(3-methoxycarbonyl-naphthalen-2-yl)-4-O-(4-methyl
-phenylsulfonyl)-L-threitol. This was dissolved in 100 ml of
dimethylformamide and, after the addition of 15.6 g of
4-benzyloxy-phenol and 15.6 g of finely ground anhydrous potassium
carbonate, stirred at 130.degree. C. under argon for 18 hours. The
reaction mixture was subsequently diluted with water and the
aqueous phase was extracted with ether. The combined ether phases
were dried over magnesium sulfate and concentrated. The
thus-obtained crude product was chromatographed on silica gel with
ether in methylene chloride. There were thus obtained 15.6 g of
1-O-(4-benzyloxy-phenyl)-2,3-O-isopropylidene-4-O-(3-methoxycarbonyl-napht
halen-2-yl)-L-threitol as a colorless oil, MS: m/z 528
([M].sup.+).
B. 1.72 g of
1-O-(4-benzyloxy-phenyl)-2,3-O-isopropylidene-4-O-(3-methoxycarbonyl-napht
halen-2-yl)-L-threitol in 40 ml of tetrahydrofuran were
exhaustively hydrogenated in a hydrogen atmosphere with the
addition of 0.2 g of palladium on charcoal (10%). Subsequently, the
reaction mixture was filtered over a 0.8.mu. cellulose filter and
the filtrate was concentrated; there was thus obtained
1-O-(4-hydroxy-phenyl)-2,3-O-isopropylidene-4-O-(3-methoxycarbonyl-naphtha
len-2-yl)-L-threitol as a colorless oil, MS: m/z 438
([M].sup.+).
C. 0.57 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
, 0.95 g of
1-O-(4-hydroxy-phenyl)-2,3-O-isopropylidene-4-O-(3-methoxycarbonyl-naphtha
len-2-yl)-L-threitol and 0.3 g of finely ground anhydrous potassium
carbonate were suspended in 10 ml of acetonitrile and stirred at
130.degree. C. under argon for 100 hours. The reaction mixture was
subsequently diluted with water and the aqueous phase was extracted
with methylene chloride. The combined methylene chloride phases
were dried over magnesium sulfate and concentrated. The
thus-obtained crude product was chromatographed on silica gel with
ether in methylene chloride. There was thus obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-(3-meth
oxycarbonyl-naphthalen-2-yl)-L-threit-1-yloxy]-phenyl]-galactitol
as a colorless solid, MS: m/z 1120.4 ([M-NH.sub.4 ].sup.+).
D. 0.58 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-(3-meth
oxycarbonyl-naphthalen-2-yl)-L-threit-1-yloxy]-phenyl]-galactitol
was dissolved in 5 ml of 2-methoxy-ethanol, treated with 5 ml of
concentrated sodium hydroxide solution and heated under reflux for
5 hours. Thereupon, the mixture was acidified with 1N hydrochloric
acid while cooling with ice, extracted with methylene chloride and
the combined methylene chloride phases were dried over magnesium
sulfate and concentrated. The thus-obtained crude product was
chromatographed on silica gel with methanol in methylene chloride.
There was thus obtained
1,6-bis-O-[4-[4-O-(3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threi
t-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol as a
colorless solid, MS: m/z 1073.2 ([M-H]).
E. 0.30 g of
1,6-bis-O-[4-[4-O-(3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threi
t-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol dissolved
in 3 ml of dimethylformamide was treated with 0.7 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.105 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.109 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with water and the mixture
was boiled briefly and filtered. There was thus obtained
1,6-bis-O-[4-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-2,3-O-isoprop
ylidene-L-threit-1-yloxy]-phenyl]-2,3:4,5-di-O-iso-propylidene-galactitol
as a colorless solid, MS: m/z 1401.7 ([M+H].sup.+).
F. 0.34 g of
1,6-bis-O-[4-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-2,3-O-isoprop
ylidene-L-threit-
l-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol was
suspended in 4 ml of dioxan, 0.5 ml of trifluoroacetic acid and 0.3
ml of water and heated under reflux at 110.degree. C. for 18 hours.
Subsequently, the reaction mixture was concentrated to dryness;
there was thus obtained
1,6-bis-O-[4-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threit-1-yl
oxy]-phenyl]-galactitol as a colorless solid, MS: m/z 1242.7
([M+H].sup.+).
G. The
1,6-bis-O-[4-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threit-1-yl
oxy]-phenyl]-galactitol obtained above was converted analogously to
Example 1.B. into
1,6-bis-O-[4-[4-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naph
thalen-2-yl]-2,3-di-O-sulfo-L-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-sulfo
-galactitol octadecasodium salt, [a]+2.3.degree.
(c 0.6; water), MS: m/z 3075.0 (reconstructed M).
EXAMPLE 51
A. 5.0 g of bis-(4-hydroxy-phenyl)-methane were dissolved in 40 ml
of ethanol, 33 ml of 1 molar sodium ethanolate solution in ethanol
and subsequently 3.6 ml of benzyl chloride were added and the
reaction mixture was heated under reflux with the exclusion of
moisture for 4 hours. Thereupon, the mixture was acidified with 1N
hydrochloric acid while cooling with ice, extracted with methylene
chloride and the combined methylene chloride phases were dried over
magnesium sulfate and concentrated. The thus-obtained crude product
was chromatographed on silica gel with ether in methylene chloride.
There was thus obtained 4-(4-benzyloxy-benzyl)-phenol in the form
of colorless crystals, MS: m/z 290 ([M].sup.+).
B. 6.0 g of
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenyl-sulfonyl)-L-threitol,
2.13 g of methyl 4-hydroxybenzoate and 1.94 g of finely ground
anhydrous potassium carbonate were suspended in 100 ml of
acetonitrile and stirred at 100.degree. C. under argon for 18
hours. Subsequently, the reaction mixture was diluted with water,
extracted with methylene chloride and the combined methylene
chloride phases were dried over magnesium sulfate and concentrated.
The residue was chromatographed on silica gel with 5% ether in
methylene chloride. There was thus obtained
2,3-O-isopropylidene-1-O-(4-methoxycarbonyl-phenyl)-4-O-(4-methyl-phenylsu
lfonyl)-L-threitol as a colorless oil, MS: m/z 450 ([M].sup.+).
C. 2.54 g of
2,3-O-isopropylidene-1-O-(4-methoxycarbonyl-phenyl)-4-O-(4-methyl-phenylsu
lfonyl)-L-threitol, 1.80 g 4-(4-benzyloxy-benzyl)-phenol and 0.86 g
of finely ground anhydrous potassium carbonate were suspended in 10
ml of dimethylformamide and stirred at 130.degree. C. under argon
for 18 hours. Subsequently, the reaction mixture was diluted with
water and extracted with methylene chloride. The combined methylene
chloride phases were dried over magnesium sulfate, concentrated and
the residue was chromatographed on silica gel with methylene
chloride. There was thus obtained
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-isopropylidene-4-O-(4-methoxycar
bonyl-phenyl)-L-threitol as a colorless solid, MS: m/z 568
([M].sup.+).
D. 2.1 g of
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-isopropylidene-4-O-(4-methoxycar
bonyl-phenyl)-L-threitol were exhaustively hydrogenated in 40 ml of
tetrahydrofuran in a hydrogen atmosphere with the addition of 0.2 g
of palladium on charcoal (10%). Subsequently, the reaction mixture
was filtered over a 0.8.mu. cellulose filter, the filtrate was
concentrated and chromatographed with 5% ether in methylene
chloride; there was thus obtained
1-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3-O-iso-propylidene-4-O-(4-methoxycarb
onyl-phenyl)-L-threitol as a colorless solid, MS: m/z 478
([M].sup.+).
E. 0.8 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
, 1.47 g of
1-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3-O-isopropylidene-4-O-(4-methoxycarbo
nyl-phenyl)-L-threitol and 0.42 g of finely ground anhydrous
potassium carbonate were suspended in 10 ml of acetonitrile and
stirred under reflux and under argon for 200 hours. Subsequently,
the reaction mixture was diluted with water, extracted with
methylene chloride and the combined methylene chloride phases were
dried over magnesium sulfate and concentrated. The residue was
chromatographed on silica gel with 7% ether in methylene chloride.
There was thus obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[4-[4-O-(4-methoxycarbonyl-phenyl
)-2,3-O-isopropylidene-L-threit-1-yloxy]-benzyl]-phenyl]-galactitol
in the form of colorless crystals, MS: m/z 1207.1
([M+Na].sup.+).
F. 1.05 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[4-[4-O-(4-methoxycarbonyl-phenyl
)-2,3-O-isopropylidene-L-threit-1-yloxy]-benzyl]-phenyl]-galactitol
were dissolved in 10 ml of 2-methoxyethanol, treated with 1 ml of
concentrated sodium hydroxide solution and 5 ml of water and heated
under reflux for 5 hours. Thereupon, the mixture was acidified with
1N hydrochloric acid while cooling with ice and the precipitate
formed was filtered off. There was thus obtained
1,6-bis-O-[4-[4-[4-O-(4-carboxy-phenyl)-2,3-O-isopropylidene-L-threit-1-yl
oxy]-benzyl]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol as a
colorless solid, MS: m/z 1178.1 ([M+Na].sup.+).
G. 0.6 g of
1,6-bis-O-[4-[4-[4-O-(4-carboxy-phenyl)-2,3-O-isopropylidene-L-threit-1-yl
oxy]-benzyl]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol
dissolved in 5 ml of dimethylformamide was treated with 0.13 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.20 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.21 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with water and the mixture
was boiled briefly and filtered. There was thus obtained
1,6-bis-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-2,3-O-isopropyliden
e-L-threit-1-yloxy]-benzyl]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol
as a colorless solid, MS: m/z 1481.0 ([M].sup.+).
H. 0.7 g of
1,6-bis-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-2,3-O-isopropyliden
e-L-threit-1-yloxy]-benzyl]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol
was suspended in 5 ml of dioxan, 1 ml of trifluoroacetic acid and 1
ml of water and heated under reflux at 100.degree. C. for 18 hours.
Subsequently, the reaction mixture was concentrated to dryness,
suspended in water and filtered; there was thus obtained
1,6-bis-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threit-1-yloxy]-b
enzyl]-phenyl]-galactitol as a colorless solid, MS: m/z 1344.3
([M+Na].sup.+).
I. The
1,6-bis-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threit-1-yloxy]-b
enzyl]-phenyl]-galactitol obtained above was converted analogously
to Example 1.B. into
1,6-bis-O-[4-[4-[4-O-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-p
henyl]-2,3-di-O-sulfo-L-threit-1-yloxy]-benzyl]-phenyl]-2,3,4,5-tetra-O-sul
fo-galactitol octadecasodium salt, [a]0.0.degree. (c 0.6; water),
MS: m/z 3158.0 (reconstructed M).
EXAMPLE 52
A. 0.50 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-2,3-O-isopropylidene-D-
threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol
(Example 48.F.) dissolved in 5 ml of dimethylformamide was treated
with 0.11 ml of 4-methyl-morpholine at 0.degree.-5.degree. C. with
the exclusion of moisture and stirred intensively for 10 minutes.
Thereupon, 0.18 g of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine
was added and the mixture was stirred at 0.degree.-5.degree. C. for
a further 2 hours. Subsequently, 0.21 g of N-methyl-D-glucamine was
added and the mixture was stirred at room temperature for a further
18 hours. Thereupon, the reaction mixture was diluted with water
and concentrated, the residue was treated with water and the
mixture was boiled briefly and filtered. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[(E)-2-(D-glucit-1-yl-methyl-carbamoyl)-vinyl]-phenyl
]-2,3-O-isopropylidene-D-threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropyliden
e-galactitol as a colorless solid, MS: m/z 1403.7
([M+Na].sup.+).
B. 0.64 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-(D-glucit-1-yl-methyl-carbamoyl)-vinyl]-phenyl
]-2,3-O-isopropylidene-D-threit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropyliden
e-galactitol was suspended in 4 ml of dioxan, 1 ml of
trifluoroacetic acid and 1 ml of water and heated under reflux at
110.degree. C. for 18 hours. Subsequently, the reaction mixture was
concentrated to dryness, treated with 10 ml of water and 0.2 ml of
triethylamine and filtered; the thus-obtained residue was dissolved
in 10 ml of acetic anhydride and 10 ml of pyridine and stirred at
room temperature for 18 hrs. The reaction mixture was subsequently
diluted with water, the aqueous phase was extracted with methylene
chloride and the combined methylene chloride phases were dried over
magnesium sulfate and concentrated. The thus-obtained crude product
was chromatographed on silica gel with 5% isopropanol in methylene
chloride. There was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[2,3-di-O-acetyl-4-O-[4-[(E)-2-[(2,3,4
,5,6-penta-O-acetyl-D-glucit-1-yl)-methyl-carbamoyl]-vinyl]-phenyl]-D-threi
t-1-yloxy]-phenyl]-galactitol as a colorless solid, MS: m/z 1978.6
([M+H].sup.+).
C. 0.34 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[2,3-di-O-acetyl-4-O-[4-[(E)-2-[(2,3,4
,5,6-penta-O-acetyl-D-glucit-1-yl)-methyl-carbamoyl]-vinyl]-phenyl]-D-threi
t-1-yloxy]-phenyl]-galactitol was dissolved in 4 ml of methanol and
4 ml of tetrahydrofuran, treated with 0.3 ml of 1 molar sodium
methylate solution in methanol and stirred at room temperature for
18 hours. The thus-formed precipitate was filtered off and washed
with methanol. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[(E)-2-(D-glucit-1-yl-methyl-carbamoyl)-vinyl]-phenyl
]-D-threit-1-yloxy]-phenyl]-galactitol as a colorless solid, MS:
m/z 1244.0 ([M+Na].sup.+).
D. The
1,6-bis-O-[4-[4-O-[4-[(E)-2-(D-glucit-1-yl-methyl-carbamoyl)-vinyl]-phenyl
]-D-threit-1-yloxy]-phenyl]-galactitol obtained above was converted
analogously to Example 1.B. into
1,6-bis-O-[4-[4-O-[4-[(E)-2-[methyl-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
)-carbamoyl]-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,
5-tetra-O-sulfo-galactitol octadecasodium salt, [a]+2.4.degree. (c
0.8; water).
EXAMPLE 53
A. 0.23 g of
1,6-bis-O-[4-[4-O-[4-[(E)-2-[methyl-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
)-carbamoyl]-vinyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,
5-tetra-O-sulfo-galactitol octadecasodium salt (Example 52.D.) was
exhaustively hydrogenated in 5 ml of distilled water in a hydrogen
atmosphere with the addition of 50 mg of palladium on charcoal
(10%). Subsequently, the reaction mixture was filtered over a
0.8.mu. cellulose filter and the filtrate was lyophilized; there
was thus obtained
1,6-bis-O-[4-[4-O-[4-[2-[methyl-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl)-ca
rbamoyl]-ethyl]-phenyl]-2,3-di-O-sulfo-D-threit-1-yloxy]-phenyl]-2,3,4,5-te
tra-O-sulfo-galactitol octadecasodium salt, [a]-2.5.degree. (c 0.6;
water), MS: m/z 3060.5 (reconstructed M).
EXAMPLE 54
A. 1.42 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-(4-methyl-phenylsulfonyl)-galactitol
, 1.25 g 3-benzyloxy-naphthalen-2-ol (E. Weber et al., Chem. Ber.
122, 959 (1989)) and 1.40 g of finely ground anhydrous potassium
carbonate were suspended in 20 ml of dimethylformamide and stirred
at 100.degree. C. under argon for 16 hours. Subsequently, the
reaction mixture was diluted with ice-water and the precipitate
formed was filtered off and dissolved in methylene chloride. The
methylene chloride phase was dried over magnesium sulfate and
concentrated. There was obtained
1,6-bis-O-(3-benzyloxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galact
itol in the form of colorless crystals, MS: m/z 726
([M].sup.+).
B. 1.4 g of
1,6-bis-O-(3-benzyloxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galact
itol were exhaustively hydrogenated in 50 ml of ethyl acetate in a
hydrogen atmosphere with the addition of 0.25 g of palladium on
charcoal (10%). The reaction mixture was subsequently filtered over
a 0.8.mu. cellulose filter, the filtrate was concentrated and the
residue was recrystallized from ether/hexane; there was thus
obtained
1,6-bis-O-(3-hydroxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galactit
ol as a colorless solid, MS: m/z 546 ([M].sup.+).
C. 3.76 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenylsulfonyl)-L-threitol,
1.60 g of methyl 3-hydroxy-naphthalene-2-carboxylate and 1.3 g of
finely ground anhydrous potassium carbonate were suspended in 50 ml
of acetonitrile and stirred under reflux and under argon for 60
hours. The reaction mixture was subsequently diluted with water and
extracted with methylene chloride. The combined methylene chloride
phases were dried over magnesium sulfate, concentrated and the
residue was chromatographed on silica gel with 5% ether in
methylene chloride. There was thus obtained
2,3-O-isopropylidene-1-O-(3-methoxycarbonyl-naphthalen-2-yl)-4-O-(4-methyl
-phenylsulfonyl)-L-threitol as a colorless oil, MS: m/z 500
([M].sup.+).
D. 1.3 g of
2,3-O-isopropylidene-1-O-(3-methoxycarbonyl-naphthalen-2-yl)-4-O-(4-methyl
-phenylsulfonyl)-L-threitol, 0.62 g of
1,6-bis-O-(3-hydroxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galactit
ol and 0.48 g of finely ground anhydrous potassium carbonate were
suspended in 20 ml of dimethyl-formamide and stirred at 100.degree.
C. under argon for 8 hours. Subsequently, the reaction mixture was
diluted with water and extracted with methylene chloride. The
combined methylene chloride phases were dried over magnesium
sulfate and concentrated, and the residue was chromatographed on
silica gel with 5% ether in methylene chloride. There was thus
obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[3-[2,3-O-isopropylidene-4-O-(3-meth
oxycarbonyl-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen-2-yl]-galactitol
as a colorless solid, MS: m/z 1220.5 ([M+NH.sub.4 ].sup.+).
E. 0.9 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[3-[2,3-O-isopropylidene-4-O-(3-meth
oxycarbonyl-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen-2-yl]-galactitol
was dissolved in 10 ml of 2-methoxyethanol, treated with 1.5 ml of
concentrated sodium hydroxide solution and 2 ml of water and heated
under reflux for 16 hrs. Thereupon, the mixture was acidified with
1N acid while acid while cooling with ice and the precipitate
formed was filtered off. There was thus obtained
1,6-bis-O-[3-[4-O-(3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threi
t-1-yloxy]-naphthalen-2-yl]-2,3:4,5-di-O-isopropylidene-galactitol
as a colorless solid, MS: m/z 1173.2 ([M-H].sup.-).
F. 0.9 g of
1,6-bis-O-[3-[4-O-(3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threi
t-1-yloxy]-naphthalen-2-yl]-2,3:4,5-di-O-isopropylidene-galactitol
was suspended in 16 ml of dioxan, 2 ml of trifluoroacetic acid and
2 ml of water and heated under reflux at 110.degree. C. for 18
hours. The reaction mixture was subsequently concentrated to
dryness and the residue was suspended in water and filtered off;
there was thus obtained
1,6-bis-O-[3-[4-O-(3-carboxy-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen
-2-yl]-galactitol as a colorless solid, MS: m/z 1013.0
([M-H].sup.-).
G. 0.75 g of
1,6-bis-O-[3-[4-O-(3-carboxy-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen
-2-yl]-galactitol was dissolved in 10 ml of acetic anhydride and 10
ml of pyridine and stirred at room temperature for 24 hrs. The
reaction mixture was subsequently diluted with water and the
precipitate formed was filtered off. This was thereupon suspended
in 20 ml of dioxan, treated with 10 ml of pyridine and 5 ml of
water and stirred at room temperature for 3 hours. Now, the
reaction mixture was again concentrated, the residue was treated
with ice-cold 1N hydrochloric acid and the thus-formed precipitate
was filtered off. There was obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[2,3-di-O-acetyl-4-O-(3-carboxy-naphth
alen-2-yl)-L-threit-1-yloxy]-naphthalen-2-yl]-galactitol as a
colorless solid, MS: m/z 1349.2 ([M-H].sup.-).
H. 0.96 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[2,3-di-O-acetyl-4-O-(3-carboxy-naphth
alen-2-yl)-L-threit- I -yloxy]-naphthalen-2-yl]-galactitol
dissolved in 7 ml of dimethylformamide was treated with 0.19 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.29 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 0.31 g of D-glucamine was added and the
mixture was stirred at room temperature for a further 18 hours.
Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with water and the mixture
was boiled briefly and filtered. There was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[2,3-di-O-acetyl-4-O-(3-D-glucit-1-ylc
arbamoyl-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen-2-yl]-galactitol
as a colorless solid, MS: m/z 1678 ([M+H].sup.+).
I. 0.50 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[3-[2,3-di-O-acetyl-O-(3-D-glucit-1-ylcar
bamoyl-naphthalen-2-yl)-L-threit-1-yloxy]-naphthalen-2-yl]-galactitol
was dissolved in 8 ml of methanol and 8 ml of tetrahydrofuran,
treated with 0.6 ml of 1 molar sodium methylate solution in
methanol and the reaction mixture was stirred at room temperature
for 18 hours. The precipitate which thereby formed was filtered off
and washed with methanol. There was thus obtained
1,6-bis-O-[3-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threit-1-yl
oxy]-naphthalen-2-yl]-galactitol as a colorless solid, MS: m/z
1341.2 ([M+H].sup.+).
K. The
1,6-bis-O-[3-[4-O-(3-D-glucit-1-ylcarbamoyl-naphthalen-2-yl)-L-threit-1-yl
oxy]-naphthalen-2-yl]-galactitol obtained above was converted
analogously to Example 1.B. into
1,6-bis-O-[3-[4-O-[3-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylcarbamoyl)-naph
thalen-2-yl]-2,3-di-O-sulfo-L-threit-1-yloxy]-naphthalen-2-yl]-2,3,4,5-tetr
a-O-sulfo-galactitol octadecasodium salt, [a]+6.1.degree. (c 0.9;
water).
EXAMPLE 55
A. 9.5 g of
2,3-O-isopropylidene-1,4-bis-O-(4-methyl-phenyl-sulfonyl)-L-threitol
and 5.86 g of 4-(4-benzyloxy-benzyl)-phenol (Example 51.A.) were
reacted at 100.degree. C. for 6 hours in 300 ml of
dimethylformamide with the addition of 27.9 g of potassium
carbonate. The reaction mixture was subsequently worked up
extractively with ice-water and methylene chloride. The crude
product was chromatographed on silica gel with n-hexane/ethyl
acetate. There was thus obtained
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-isopropylidene-4-O-(4-methyl-phe
nylsulfonyl)-L-threitol as a colorless oil, MS: m/z 588.0
([M].sup.+).
B. 3.0 g of
1-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-iso-propylidene-4-O-(4-methyl-ph
enylsulfonyl)-L-threitol, 1.0 g of
1,6-bis-O-(4-hydroxy-phenyl)-2,3:4,5-di-O-isopropylidene-galactitol
(Example 48.B.) and 0.93 g of finely ground anhydrous potassium
carbonate were suspended in 30 ml of dimethylformamide and stirred
at 100.degree. C. under argon for 48 hours. The reaction mixture
was subsequently diluted with water and extracted with ether. The
combined ether phases were dried over magnesium sulfate,
concentrated and the residue was chromatographed on silica gel with
5% ether in methylene chloride. There was thus obtained
1,6-bis-O-[4-[4-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-isopropylidene-L-t
hreit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol as a
yellowish oil, MS: m/z 1296.4 ([M+NH.sub.4 ].sup.+).
C. 0.5 g of
1,6-bis-O-[4-[4-O-[4-(4-benzyloxy-benzyl)-phenyl]-2,3-O-isopropylidene-L-t
hreit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol was
exhaustively hydrogenated in 10 ml of tetrahydrofuran in a hydrogen
atmosphere with the addition of 0.1 g of palladium on charcoal
(10%). Subsequently, the reaction mixture was filtered over a
0.8.mu. cellulose filter and the filtrate was concentrated: there
was thus obtained
1,6-bis-O-[4-[4-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3-O-isopropylidene-L-thr
eit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol as a
colorless solid, MS: m/z 1097.2 ([M-H].sup.-).
D. 1.0 g of
1,6-bis-O-[4-[4-O-[4-(4-hydroxy-benzyl)-phenyl]-2,3-O-isopropylidene-L-thr
eit-1-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol, 0.9 g
of
2,3-O-isopropylidene-1-O-(4-methoxycarbonyl-phenyl)-4-O-(4-methyl-phenylsu
lfonyl)-L-threitol (Example 51.B.) and 1.0 g of finely ground
anhydrous potassium carbonate were suspended in 3 ml of
dimethylformamide and stirred at 100.degree. C. under argon for 18
hours. The reaction mixture was subsequently diluted with water and
extracted with ether. The combined ether phases were dried over
magnesium sulfate and concentrated. The residue was chromatographed
on silica gel with 2%-5% ether in methylene chloride. There was
thus obtained
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-[4-[4-[
2,3-O-isopropylidene-4-O-(4-methoxycarbonyl-phenyl)-L-threit-1-yloxy]-benzy
l]-phenyl]-L-threit-1-yloxy]-phenyl]-galactitol as a colorless
solid, MS: m/z 1673.8 ([M+NH.sub.4 ].sup.+).
E. 0.428 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[4-[2,3-O-isopropylidene-4-O-[4-[4-[
2,3-O-isopropylidene-4-O-(4-methoxycarbonyl-phenyl)-L-threit-1-yloxy]-benzy
l]-phenyl]-L-threit-1-yloxy]-phenyl]-galactitol was dissolved in 5
ml of 2-methoxyethanol, treated with 1 ml of concentrated sodium
hydroxide solution and 0.5 ml of water and heated under reflux for
3 hrs. Thereupon, the mixture was acidified with 1N hydrochloric
acid while cooling with ice and the precipitate which formed was
filtered off. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-carboxy-phenyl-2,3-O-isopropylidene-L-thre
it-1-yloxy]-benzyl]-phenyl]-2,3-O-isopropylidene-L-threit-1-yloxy]-phenyl]-
2,3:4,5-di-O-isopropylidene-galactitol as a colorless solid, MS:
m/z 1626.5 ([M-H].sup.-).
F. 0.345 g of
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-carboxy-phenyl)-2,3-O-isopropylidene-L-thr
eit-1-yloxy]-benzyl]-phenyl]-2,3-O-isopropylidene-L-threit-1-yloxy]-phenyl]
-2,3:4,5-di-O-isopropylidene-galactitol dissolved in 2 ml of
dimethylformamide was treated with 0.1 ml of 4-methylmorpholine at
0.degree.-5.degree. C. with the exclusion of moisture and stirred
intensively for 10 minutes.
Thereupon, 0.08 g of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine
was added and the mixture was stirred at 0.degree.-5.degree. C. for
a further 2 hours. Subsequently, 0.085 g of D-glucamine was added
and the mixture was stirred at room temperature for a further 18
hours. Thereupon, the reaction mixture was diluted with water and
concentrated, the residue was treated with water and the mixture
was boiled briefly and filtered. There was thus obtained
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-2,3-O-isopr
opylidene-L-threit-1-yloxy]-benzyl]-phenyl]-2,3-O-isopropylidene-L-threit-1
-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol as a
colorless solid, MS: m/z 1953.4 ([M+H].sup.+).
G. 0.38 g of
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-2,3-O-isopr
opylidene-L-threit-1-yloxy]-benzyl]-phenyl]-2,3-O-isopropylidene-L-threit-1
-yloxy]-phenyl]-2,3:4,5-di-O-isopropylidene-galactitol was
suspended in 9 ml of dioxan, 1.6 ml of trifluoroacetic acid and 3
ml of water and heated at 110.degree. C. under reflux for 18 hours.
Subsequently, the reaction mixture was concentrated to dryness, the
residue was suspended in water and the suspension was filtered;
there was thus obtained
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threit-1-
yloxy]-benzyl]-phenyl]-L-threit-1-yloxy]-phenyl]-galactitol as a
colorless solid, MS: m/z 1737.8 ([M+Na].sup.+).
H. The
1,6-bis-O-[4-[4-O-[4-[4-[4-O-(4-D-glucit-1-ylcarbamoyl-phenyl)-L-threit-1-
yloxy]-benzyl]-phenyl]-L-threit-1-yloxy]-phenyl]-galactitol
obtained above was converted analogously to Example 1.B. into
1,6-bis-O-[4-[4-O-[4-[4-[4-O-[4-(2,3,4,5
sulfo-D-glucit-1-ylcarbamoyl)-phenyl]-2,3-di-O-sulfo-L-threit-1-yloxy]-ben
zyl]-phenyl]-2,3-di-O-sulfo-L-threit-1-yloxy]-phenyl]-2,3,4,5-tetra-O-sulfo
-galactitol docosodium salt, [a]+4.7.degree. (c 0.6; water), MS:
m/z 3959.0 (reconstructed M).
EXAMPLE 56
A. 1.2 g of
1,6-bis-O-(3-carboxy-naphthalen-1-yl)-2,3:4,5-di-O-isopropylidene-galactit
ol (Example 19.A.) were suspended in 15 ml of dioxan, 5 ml of
trifluoroacetic acid and 5 ml of water and heated under reflux at
110.degree. C. for 17 hours. Thereupon, the reaction mixture was
concentrated the residue was treated with water and the mixture was
filtered. There was thus obtained
1,6-bis-O-(3-carboxy-naphthalen-1-yl)-galactitol as a colorless
solid, MS: m/z 521.2 ([M-H].sup.-).
B. 0.96 g of 1,6-bis-O-(3-carboxy-naphthalen-1-yl)-galactitol
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-naphthalen-1-yl)-galactitol
was stirred at room temperature in a mixture of 6 ml of acetic
anhydride and 11 ml of pyridine for 18 hours. Thereupon, the
reaction mixture was concentrated, the residue was treated with
ice-water and dilute hydrochloric acid and the thus-formed
precipitate was filtered off. There was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-naphthalen-1-yl)-galactitol
as a colorless solid, MS: m/z 689.2 ([M-H].sup.-).
C. A solution of 30 g of benzyl
2-benzyloxycarbonylamino-2-desoxy-a-D-glucopyranoside (Heyns and
Paulsen, Chem. Ber. 88, 188 (1955)) in 116 ml of pyridine was
treated at 0.degree. C. with a solution of 19.85 g of
p-tolylsulfonyl chloride in 30 ml of dichloromethane and stirred at
room temperature for 4 hours. Then, the mixture was poured into
ice-cold 2N sulfuric acid and extracted with dichloromethane. The
organic phases were washed with aqueous sodium hydrogen carbonate
solution, dried over magnesium sulfate and concentrated. The
residue was chromatographed over silica gel with hexane/ethyl
acetate and gave benzyl
2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-a-D-glucopyranosid
e, [a]+101.8.degree. (c 0.5; dioxan), MS: m/z 580
([M+Na].sup.+).
D. A solution of 32.14 g benzyl
2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-a-D-glucopyranosid
e in 75 ml of dimethyl sulfoxide was treated at room temperature
with 7.5 g of sodium azide and stirred at 90.degree. C. for 3
hours. The mixture was then poured on to ice/water. Separated
crystals were filtered off under suction, washed with water and
dried. There was obtained benzyl
6-azido-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranoside,
[a]+119.60.degree. (c 0.5; dioxan), MS: m/z 428 ([M+H].sup.+).
E. A solution of 1.1 g of benzyl
6-azido-2-benzyloxycarbonyl-amino-2,6-didesoxy-a-D-glucopyranoside
in 7.5 ml of tetra-hydrofuran and 69 .mu.l water was treated with
674 mg of triphenylphosphine at room temperature and stirred for 24
hours. Then, 1 ml of water was added to the thick slurry and the
mixture was stirred for a further 30 minutes and concentrated. The
residue was crystallized from methanol and gave benzyl
6-amino-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranoside,
[a]+124.2.degree. (c 0.6; acetone), MS: m/z 403 ([M+H].sup.+).
F. A suspension of 3.0 g of benzyl
6-amino-2-benzyloxy-carbonylamino-2,6-didesoxy-a-D-glucopyranoside
and 1.33 g of D-gluconic acid g-lactone in 60 ml of dioxan was
brought into solution at 80.degree. C. and held at this temperature
for a further 18 hours. The separated product was filtered off
under suction, washed with dioxan and dried to give D-gluconic acid
(benzyl
2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide,
[a]+120.0.degree. (c 0.2; dioxan), MS: m/z 603.2
([M+Na].sup.+).
G. A solution of 1.4 g of D-gluconic acid (benzyl
2-benzyloxy-carbonylamino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide
in 5 ml of pyridine was acetylated with 2 ml of acetic acid at room
temperature for 18 hours and concentrated to give
2,3,4,5,6-penta-O-acetyl-D-gluconic acid (benzyl
3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranosid-6
-yl)-amide, [a]+84.0.degree. (c 0.2; dioxan), MS: m/z 897.3
([M+Na].sup.+).
H. A solution of 250 mg of 2,3,4,5,6-penta-O-acetyl-D-gluconic acid
(benzyl
3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranosid-6
-yl)-amide in 20 ml of dioxan and 2 ml water was hydrogenated at
room temperature in the presence of palladium on charcoal (10%).
After 2 hours, the catalyst was filtered off over a filter aid and
the filtrate was concentrated. The residue was crystallized from
ethyl acetate/ether and gave 2,3,4,5,6-penta-O-acetyl-D-gluconic
acid (benzyl
3,4-di-O-acetyl-2-amino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide,
[a]+96.0.degree. (c 0.2; dioxan), MS: m/z 741.1 ([M+H].sup.+).
I. A solution of 0.60 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-(3-carboxy-naphthalen-1-yl)-galactitol
in 8 ml of dimethylformamide was treated with 0.21 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.31 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 1.27 g of 2,3,4,5,6-penta-O-acetyl-D-gluconic
acid (benzyl
3,4-di-O-acetyl-2-amino-2,6-didesoxy-a-D-gluco-pyranosid-6-yl)-amide
were added and the mixture was stirred at room temperature for a
further 18 hours. Thereupon, the reaction mixture was diluted
several times with water, evaporated at 40.degree.-50.degree. C.
under reduced pressure and the residue was partitioned between
water/methanol and methylene chloride. The combined methylene
chloride phases were dried over magnesium sulfate, filtered and
concentrated, and the thus-obtained residue was chromatographed on
silica gel with methylene chloride/ methanol; there was thus
obtained 1,6-bis-O-[3-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-acetyl-D-gluconoylamino)-3,4-di-O-acetyl
-a-D-glucopyranosid-2-ylcarbamoyl]-naphthalen-1-yl]-2,3,4,5-tetra-O-acetyl-
galactitol as a colorless solid, MS: m/z 2157.4 ([M+Na].sup.+).
K. 0.71 g of 1,6-bis-O-[3-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-acetyl-D-gluconoylamino)-3,4-di-O-acetyl
-a-D-glucopyranosid-2-ylcarbamoyl]-naphthalen-1-yl]-2,3,4,5-tetra-O-acetyl-
galactitol was dissolved in 8 ml of methanol and 8 ml of
tetrahydrofuran, treated with 0.3 ml of 1 molar sodium methylate
solution in methanol and stirred at room temperature for 18 hours.
The precipitate which thereby formed was filtered off. There was
thus obtained 1,6-bis-O-[3-(benzyl
2,6-didesoxy-6-D-gluconoylamino-a-D-glucopyranosid-2-ylcarbamoyl)-naphthal
en-1-yl]-galactitol as a colorless solid, MS: m/z 1401.7
([M+Na].sup.+).
L. The 1,6-bis-O-[3-(benzyl
2,6-didesoxy-6-D-gluconoylamino-a-D-glucopyranosid-2-ylcarbamoyl)-naphthal
en-1-yl]-galactitol obtained above was converted analogously to
Example 1.B. into 1,6-bis-O-[3-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoylamino)-3,4-di-O-sulfo-a
-D-glucopyranosid-2-ylcarbamoyl]-naphthalen-1-yl]-2,3,4,5-tetra-O-sulfo-gal
actitol octadecasodium salt, [a]+60.9.degree. (c 0.7; water), MS:
m/z 3216.5 (reconstructed M).
EXAMPLE 57
A. 5.3 g of
2,3:4,5-di-O-isopropylidene-1,6-bis-O-[(E)-4-(2-methoxycarbonyl-vinyl)-phe
nyl]-galactitol (Example 3.A.) were suspended in 120 ml of dioxan,
15 ml of trifluoroacetic acid and 30 ml of water and heated under
reflux at 110.degree. C. for 4 hours. Thereupon, the reaction
mixture was concentrated, the residue was treated with water and
the mixture was filtered. There was thus obtained
1,6-bis-O-[4-[(E)-2-methoxycarbonyl-vinyl]-phenyl]-galactitol as a
colorless solid, MS: m/z 502 ([M].sup.+).
B. 4.5 g of
1,6-bis-O-[4-[(E)-2-methoxycarbonyl-vinyl]-phenyl]-galactitol, 50
ml of methanol and 40 ml of concentrated aqueous sodium hydroxide
solution were heated under reflux at 110.degree. C. for 24 hours.
Thereupon, the majority of the methanol was distilled off under
reduced pressure, the residue was diluted with ice-water, acidified
with dilute aqueous hydrochloric acid and the crystals which
thereby formed were filtered off. There was thus obtained
1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-galactitol in the form
of colorless crystals, MS: m/z 473.4 ([M-H].sup.-).
C. 4.23 g of 1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-galactitol
were stirred at room temperature in a mixture of 25 ml of acetic
anhydride and 50 ml of pyridine for 18 hours. Thereupon, the
reaction mixture was concentrated and the residue was treated with
ice-water and dilute hydrochloric acid. The thus-formed precipitate
was filtered off, dissolved in 95 ml of dioxan, treated with 50 ml
of pyridine and 15 ml of water and stirred at room temperature for
a further 3 hours; thereupon the mixture was concentrated, the
residue was treated with ice-water and dilute hydrochloric acid and
the thus-formed precipitate was filtered off. There was thus
obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-galactit
ol as a colorless solid, MS: m/z 641.2 ([M-H].sup.-).
D. 0.55 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-carboxy-vinyl]-phenyl]-galactit
ol in 8 ml of dimethylformamide was treated with 0.21 ml of
4-methylmorpholine at 0.degree.-5.degree. C. with the exclusion of
moisture and stirred intensively for 10 minutes. Thereupon, 0.31 g
of solid 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and the
mixture was stirred at 0.degree.-5.degree. C. for a further 2
hours. Subsequently, 1.27 g of 2,3,4,5,6-penta-O-acetyl-D-gluconic
acid (benzyl
3,4-di-O-acetyl-2-amino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide
(Example 56.H.) were added and the mixture was stirred at room
temperature for a further 18 hours. Thereupon, the reaction mixture
was diluted several times with water, evaporated at
40.degree.-50.degree. C. under reduced pressure and the residue was
partitioned between water/methanol and methylene chloride. The
combined methylene chloride phases were dried over magnesium
sulfate, filtered and concentrated, and the thus-obtained residue
was chromatographed on silica gel with methylene chloride/methanol;
there was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-acetyl-D-gluconoylamino)
-a-D-glucopyranosid-2-ylcarbamoyl]-vinyl]-phenyl]-galactitol as a
colorless solid, MS: m/z 2088.4 ([M+H].sup.+).
E. 0.44 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-[benzyl-3,4-di-O-acetyl-2,6-did
esoxy-6-(2,3,4,5,6-penta-O-acetyl-D-gluconoylamino)-a-D-glucopyranosid-2-yl
carbamoyl]-vinyl]-phenyl]-galactitol was dissolved in 5 ml of
methanol and 5 ml of tetrahydrofuran, treated with 0.2 ml of 1
molar sodium methylate solution in methanol and stirred at room
temperature for 18 hours. The precipitate which thereby formed was
filtered off. There was thus obtained 1,6-bis-O-[4-[(E)-2-(benzyl
2,6-didesoxy-6-D-gluconoylamino-a-D-glucopyranoside-2-ylcarbamoyl)-vinyl]-
phenyl]-galactitol as a colorless solid, MS: m/z 1354.5
([M+Na].sup.+).
F. The
1,6-bis-O-[4-[(E)-2-(benzyl-2,6-didesoxy-6-D-gluconoylamino-a-D-glucopyran
osid-2-ylcarbamoyl)-vinyl]-phenyl]-galactitol obtained above was
converted analogously to Example 1.B. into
1,6-bis-O-[4-[(E)-2-[benzyl
2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoylamino)-3,4-di-O-sulfo-a
-D-glucopyranosid-2-ylcarbamoyl]-vinyl]-phenyl]-2,3,4,5-tetra-O-sulfo-galac
titol octadecasodium salt, [a]+45.6.degree. (c 0.7; water), MS: m/z
316.75 (reconstructed M).
EXAMPLE 58
A. 0.88 g of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-[benzyl-3,4-di-O-acetyl-2,6-did
esoxy-6-(2,3,4,5,6-penta-O-acetyl-D-gluconoylamino)-a-D-glucopyranosid-2-yl
carbamoyl]-vinyl]-phenyl]-galactitol (Example 57.D.) was
exhaustively hydrogenated in 20 ml of tetrahydrofuran in a hydrogen
atmosphere with the addition of 350 mg of palladium on charcoal
(10%). Subsequently, the reaction mixture was filtered over a
0.8.mu. cellulose filter and concentrated. The thus-obtained
residue was chromatographed on silica gel with methylene chloride/
methanol; there was thus obtained
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[2-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-acetyl-gluconoylamino)-a
-D-glucopyranosid-2-ylcarbamoyl]-ethyl]-phenyl]-galactitol as a
colorless oil, MS: m/z 2114.5 ([M+Na].sup.+).
B. 0.24 g of 2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[2-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-acetyl-gluconoylamino)-a
-D-glucopyranosid-2-ylcarbamoyl]-ethyl]-phenyl]-galactitol was
dissolved in 2 ml of methanol and 2 ml of tetrahydrofuran, treated
with 0.15 ml of 1 molar sodium methylate solution in methanol and
stirred at room temperature for 18 hours. The precipitate which
thereby formed was filtered off. There was thus obtained
1,6-bis-O-[4-[2-(benzyl
2,6-didesoxy-6-gluconoylamino-a-D-glucopyranosid-2-ylcarbamoyl)-ethyl]-phe
nyl]-galactitol as a colorless solid, MS: m/z 1357.4
([M+Na].sup.+).
C. The 1,6-bis-O-[4-[2-(benzyl
2,6-didesoxy-6-gluconoylamino-a-D-glucopyranosid-2-ylcarbamoyl)-ethyl]-phe
nyl]-galactitol obtained above was converted analogously to Example
1.B. into
1,6-bis-O-[4-[2-[benzyl-2,6-didesoxy-6-(2,3,4,5,6-penta-O-sulfo-D-gluconoy
lamino)-3,4-di-O-sulfo-a-D-glucopyranosid-2-ylcarbamoyl]-ethyl]-phenyl]-2,3
,4,5-tetra-O-sulfo-galactitol octadecasodium salt, [a]+48.8.degree.
(c 0.5; water), MS: m/z 3172.5 (reconstructed M).
EXAMPLE 59
A. A solution of 7.4 g of 4-fluoro-3-nitro-benzoic acid in 100 ml
of dimethylformamide was treated with 16.0 g of D-glucamine and
stirred at room temperature for 4 hours. After the addition of 6 ml
of triethylamine, the mixture was stirred at 40.degree. C. for a
further 16 hours. The reaction solution was evaporated. The residue
was stirred at room temperature with 400 ml of pyridine and 200 ml
of acetic anhydride for 5 hours. After concentration, the residue
obtained was treated with water and acidified to pH 2-3 with 5%
hydrochloric acid solution and extracted with ethyl acetate. The
organic extracts were washed with ice-water and saturated sodium
chloride solution, dried over magnesium sulfate and evaporated. The
residue was chromatographed over silica gel with ethyl acetate. The
product fractions were concentrated and the residue was
crystallized from ether to give
4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-3-nitro-benzoic
acid as yellow crystals, [a]-23.0.degree. (c 0.5; DMSO), MS: m/z
579.7 ([M+Na].sup.+).
B. 8.78 g of 2-chloro-2,4-dimethoxy-1,3,5-triazine were added to a
solution of 27.8 g of
4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-3-nitro-benzoic
acid and 5.32 g of 4-methylmorpholine in 150 ml of absolute
dimethylformamide at 0.degree.C. The reaction mixture was stirred
at this temperature for 2 hours and then treated with 14.0 g of
benzyl 2-amino-2-desoxy-a-D-glucopyranoside (Meyer zu Reckendorf,
Chem. Ber. 107, 869 (1974)). The mixture was stirred for a further
18 hours and then concentrated in a vacuum. The residual syrup was
purified by chromatography on silica gel with methylene
chloride/isopropanol and gave benzyl
2-desoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoy
lamino]-a-D-glucopyranoside, [a]+33.6.degree. (c 0.5; DMSO), MS:
m/z 808.4 ([M+H].sup.+).
C. 10.9 g of p-toluenesulfonyl chloride were added in portions to a
solution of 30.0 g of benzyl
2-desoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoy
lamino]-a-D-glucopyranoside in 250 ml of absolute pyridine. After
completion of the addition, the reaction mixture was stirred at
room temperature for 7 hours and then concentrated. The residue was
taken up in ethyl acetate and extracted with water. The organic
phases were washed with dilute sulfuric acid, water and saturated
sodium chloride solution, dried over magnesium sulfate and
evaporated. The residue was chromatographed on silica gel with
methylene chloride/isopropanol and gave benzyl
2-desoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoy
lamino]-6-O-(p-tolylsulfonyl)-a-D-gluco-pyranoside,
[a]+31.4.degree. (c 0.5; DMSO), MS: m/z 984.7 ([M+K].sup.+).
D. 6.5 g of sodium azide were added to a solution of 31.0 g of
benzyl
2-desoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoy
lamino]-6-O-(p-tolylsulfonyl)-a-D-glucopyranoside in 250 ml of
absolute dimethylformamide. The reaction mixture was stirred at
65.degree. C. for 6 hours and then concentrated. The residue was
poured into ice-water and extracted with ethyl acetate. The organic
phases were washed with water and saturated sodium chloride
solution, dried over magnesium sulfate and evaporated. The residue
was chromatographed on silica gel with methylene
chloride/isopropanol and gave benzyl
6-azido-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside, [a]+30.2.degree. (c 0.5;
DMSO), MS: m/z 855.6 ([M+Na].sup.+).
E. 2.15 g of triphenylphosphine were added to a solution of 4.16 g
of benzyl
6-azido-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-gluci
t-1-ylamino)-benzoylamino]-a-D-glucopyranoside in 50 ml of
tetrahydrofuran and 1.8 ml of water and the mixture was stirred at
room temperature for 20 hours and then concentrated. The residue
was chromatographed over silica gel with ethyl acetate/methanol and
gave benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside, [a]+37.4.degree. (c 0.5;
DMSO), MS: m/z 829.7 ([M+Na].sup.+).
F. 2-Chloro-2,4-dimethoxy-1,3,5-triazine was added to a solution of
301 mg of
1,6-bis-O-(6-carboxy-naphthalen-2-yl)-2,3:4,5-di-O-isopropylidene-galactit
ol (Example 16.A.) and 137 mg of N-methylmorpholine in 3 ml of
absolute dimethylformamide at 0.degree. C. The reaction mixture was
stirred at this temperature for 2 hours and then treated with 1.21
g of benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside. The reaction mixture was
stirred at room temperature for 20 hours and then concentrated. The
residue was acetylated with 20 ml of acetic anhydride in 30 ml of
pyridine and, after 5 hours at room temperature, concentrated. The
residue was then taken up in ethyl acetate and extracted with
water. The organic phases were washed with dilute sulfuric acid,
water and saturated sodium bicarbonate solution, dried over
magnesium sulfate and evaporated. The residue was chromatographed
over silica gel with ethyl acetate/ methanol and gave
1,6-bis-O-[6-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-
penta-O-acetyl-D-glucit-1-ylamino)-benzoylamino]-a-D-glucopyranosid-6-ylcar
bamoyl]-naphthalen-2-yl]-2,3:4,5-di-O-isopropylidene-galactitol,
[a]+43.6.degree. (c 0.5; chloroform), MS: m/z 2370.9
([M+Na].sup.+).
G. A solution of 1.0 g
1,6-bis-O-[6-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-
penta-O-acetyl-D-glucit
1-ylamino)-benzoylamino]-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl
]-2,3:4,5-di-O-isopropylidene-galactitol in 100 ml of 80% acetic
acid was heated on a steam bath for 3 hours and then concentrated.
The residue was acetylated with 20 ml of acetic anhydride in 30 ml
of pyridine and, after 18 hours at room temperature, concentrated.
The residue was then taken up in ethyl acetate and extracted with
water. The organic phases were washed with dilute sulfuric acid,
saturated sodium bicarbonate solution and saturated sodium chloride
solution, dried over magnesium sulfate and evaporated. The residue
was chromatographed over silica gel with methylene
chloride/isopropanol and gave
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[6-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2
-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoylamino]-a-D
-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl]-galactitol,
[a]+44.6.degree.(c 0.5; chloroform), MS: m/z 2358.9
([M+Na].sup.+).
H. A solution of 820 mg of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[6-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2
-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoylamino]-a-D
-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl]-galactitol in 24 ml
of methanol and 6 ml of dimethoxyethane was treated with 1 ml of a
2% methanolic sodium methanolate solution and stirred at room
temperature for 6 hours. The resulting precipitate was filtered off
under suction, washed with methanol and dried at 60.degree. C. in a
vacuum to give
1,6-bis-O-[6-[benzyl-2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoyla
mino)-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl]-galactitol,
[a]+33.5.degree. (c 0.5; dimethyl sulfoxide), MS: m/z 1701.8
(M+Na).sup.+.
I. Sulfation of 1,6-bis-O-[6-[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoylamino)-a-D-glucopyrano
sid-6-ylcarbamoyl]-naphthalen-2-yl]-galactitol as described in Ex.
26.C. gave 1,6-bis-O-[6-[benzyl
2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamino)-ben
zoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-yl
]-2,3,4,5-tetra-O-sulfo-galactitol octadecasodium salt,
[a]+43.2.degree. (c 0.5; water), MS: m/z 3515 (reconstructed
M).
EXAMPLE 60
A. Reaction of benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside (Example 59.E.) with
4,4'-dioxo-5,5'-(2-acetoxy-propan-1,3-diyldioxy)-di-4H-1-benzopyran-2-carb
oxylic acid (prepared from 4,4'-dioxo-5,5'-(2-hydroxy-propane-1
,3-diyldioxy)-di-4H-1-benzopyran-2-carboxylic acid analogously to
Example 57.C.) as described under Ex. 59.F. gave
4,4'-dioxo-5,5'-(2-acetoxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-car
boxylic acid N,N'-bis-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-yl]-amide],
[a]+80.0.degree. (c 0.5; chloroform), MS: m/z 2370.9
([M+Na].sup.+).
B. Deacetylation of
4,4'-dioxo-5,5'-(2-acetoxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-car
boxylic acid N,N'-bis-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-yl]-amide] as
described under Ex. 59.H. gave
4,4'-dioxo-5,5'-(2-hydroxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-car
boxylic acid N,N'-bis-[[benzyl
2,6-didesoxy-2-(4-D-glucit-1-yl]-amino-3-nitro-benzoylamino)-a-D-glucopyra
nosid-6-yl]-amide], [a]+47.00 (c 0.5; dimethylsulfoxide), MS: m/z
1648.8 ([M+Na].sup.+).
C. Sulfation of
4,4'-dioxo-5,5'-(2-hydroxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-car
boxylic acid N,N'-bis-[[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoylamino)-a-D-glucopyrano
sid-6-yl]-amide] as described under Ex. 59.1. gave
4,4'-dioxo-5,5'-(2-sulfooxy-propane-1,3-diyldioxy)-di-4H-1-benzopyran-2-ca
rboxylic acid
N,N'-bis-[[benzyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-yl
amino)-3-nitro-benzoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-yl]-amide]
pentadecasodium salt, [a]+87.0.degree.(c 0.2; water), MS: m/z
3156.5 (reconstructed M).
EXAMPLE 61
A. Reaction of benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside (Example 59.E.) with
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-((E)-2-carboxy-vinyl)-phenyl]-galactit
ol (Example 57.C.) as described under Ex. 59.F. gave
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-[benzyl-3,4-di-O-acetyl-2,6-did
esoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-3-nitro-benzoylami
no]-a-D-glucopyranosid-6-ylcarbamoyl]-vinyl]-phenyl]-galactitol,
[a]+42.4.degree. (c 0.5; chloroform), MS: m/z 2411.9
([M+Na].sup.+).
B. Deacetylation of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4-[(E)-2-[benzyl-3,4-di-O-acetyl-2,6-did
esoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-3-nitro-benzoylami
no]-a-D-glucopyranosid-6-ylcarbamoyl]-vinyl]-phenyl]-galactitol as
described under Ex. 26.C. gave 1,6-bis-O-[4-[(E)-2-[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoylamino)-a-D-glucopyrano
sid-6-ylcarbamoyl]-vinyl]-phenyl]-galactitol, [a]+45.6.degree. (c
0.5; dimethyl sulfoxide), MS: m/z 1654.8 ([M+Na].sup.+).
C. Sulfation of 1,6-bis-O-[4-[(E)-2-[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoylamino)-a-D-glucopyrano
sid-6-ylcarbamoyl]-vinyl]-phenyl]-galactitol as described under
Example 26.C. gave 1,6-bis-O-[4-[(E)-2-[benzyl
2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamino)-3-nitro-ben
zoyl-amino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbamoyl]-vinyl]-phenyl]
-2,3,4,5-tetra-O-sulfo-galactitol octadecasodium salt,
[a]+40.2.degree. (c 0.2; water), MS: m/z 3469.0 (reconstructed
M).
EXAMPLE 62
A. Reaction of benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside (Example 59.E.) with
1,4-bis-O-[3-carboxy-naphthalen-2-yl)-2,3-O-isopropylidene-L-threitol
(Example 13.A.) as described under Ex. 59.F. gave
1,4-bis-O-[3-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-
acetyl-D-glucit-1-ylamino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-ylcar
bamoyl]-naphthalen-2-yl]-2,3-O-isopropylidene-L-threitol,
[a]+63,4.degree. (c 0,5; chloroform), MS: m/z 2271.0
([M+Na].sup.+).
B. Reaction of
1,4-bis-O-[3-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-
acetyl-D-glucit-1-ylamino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-ylcar
bamoyl]-naphthalen-2-yl]-2,3-O-isopropylidene-L-threitol as
described under Ex. 59.G. gave 2,3-di-O-acetyl-1,4-bis-O-[3-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-
yl]-L-threitol, [a]+62.4.degree. (c 0.5; chloroform), MS: n/z
2315.9 ([M+Na].sup.+).
C. Deacetylation of 2,3-di-O-acetyl-1,4-bis-O-[3-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-3-nitro-benzoylamino]-a-D-glucopyranosid-6-ylcarbamoyl]-naphthalen-2-
yl]-L-threitol as described under Ex. 59.H. gave
1,4-bis-O-[3-[benzyl-2,6-didesoxy-2-(4-D-glucit-1-ylamino)-3-nitro-benzoyl
amino)-a-D-glucopyranosid-6-yl-carbamoyl]-naphthalen-2-yl]-L-threitol,
[a]+68.8.degree. (c 0.5; dimethyl sulfoxide), MS: m/z 1642.3
([M+Na].sup.+).
D. Sulfation of 1,4-bis-O-[3-[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino)-3-nitro-benzoylamino)-a-D-glucopyran
osid-6-ylcarbamoyl]-naphthalen-2-yl]-L-threitol as described under
Ex. 26.C. gave
1,4-bis-O-[3-[benzyl-2,6-didesoxy-2-[4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1
-ylamino)-3-nitro-benzoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarba
moyl]-naphthalen-2-yl]-2,3-di-O-sulfo-L-threitol hexadecasodium
salt, [a]+49.6.degree. (c 0.5; water), MS: m/z 3252.5
(reconstructed M).
EXAMPLE 63
A. Reaction of benzyl
6-amino-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-yla
mino)-benzoylamino]-a-D-glucopyranoside (Example 59.E.) with
1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,3:4,5-di-O-isopropylidene-galactito
l (Example 1 2.B.) as described under Ex. 59.F. gave
1,6-bis-O-[4'-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-gluc
it-1-ylamino)-benzoylamino]-a-D-glucopyranosid-6-ylcarbamoyl]-biphenyl-4-yl
]-2,3:4,5-di-O-isopropylidene-galactitol, MS: m/z 2422.8
([M+Na].sup.+).
B. Reaction of 1,6-bis-O-[4'-[benzyl
3,4-di-O-acetyl-2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-gluc
it-1-ylamino)-benzoylamino]-a-D-glucopyranosid-6-ylcarbamoyl]-biphenyl-4-yl
]-2,3:4,5-di-O-isopropylidene-galactitol as described under Ex.
59.G. gave 2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4'-[benzyl
3,4-di-O-acetyl-2,6 -didesoxy-2-[3-nitro-4-(2,3,4,
5,6-penta-O-actyl-D-glucit-1-ylamino)-benzoylamino]-a-D-glucopyranosid-6-y
lcarbamoyl]-biphenyl-4-yl]-galactitol, [a]+49.8.degree. (c 0.5;
chloroform), MS: m/z 2510.8 ([M+Na].sup.+).
C. Deacetylation of
2,3,4,5-tetra-O-acetyl-1,6-bis-O-[4'-[benzyl-3,4-di-O-acetyl-2,6-didesoxy-
2-[3-nitro-4-(2,3,4,5,6-penta-O-acetyl-D-glucit-1-ylamino)-benzoylamino]-a-
D-glucopyranosid-6-ylcarbamoyl]-biphenyl-4-yl]-galactitol as
described under Ex. 59.H. gave
1,6-bis-O-[4'-[benzyl-2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoyl
amino)-a-D-glucopyranosid-6-ylcarbamoyl]-biphenyl-4-yl]-galactitol,
[a]+32.0.degree. (c 0.5; dimethyl sulfoxide).
D. Sulfation of 1,6-bis-O-[4'-[benzyl
2,6-didesoxy-2-(4-D-glucit-1-ylamino-3-nitro-benzoylamino)-a-D-glucopyrano
sid-6-ylcarbamoyl]-biphenyl-4-yl]-galactitol as described under Ex.
26.C. gave 1,6-bis-O-[4'-[benzyl
2,6-didesoxy-2-[3-nitro-4-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamino)-ben
zoylamino]-3,4-di-O-sulfo-a-D-glucopyranosid-6-ylcarbamoyl]-biphenyl-4-yl]-
2,3,4,5-tetra-O-sulfo-galactitol octadecasodium salt,
[a]+41.5.degree. (c 0.5; water), MS: m/z 3269.0 (reconstructed
M).
EXAMPLE 64
A. 13.80 g of 4-hydroxy-benzoic acid and 45.20 g of
tert.-butyl-dimethylchlorosilane were stirred at room temperature
under argon for 18 hours with the addition of 40.80 g of imidazole
in 500 ml of dimethylformamide. The solvent was distilled off in a
water-jet vacuum and the residue was worked up extractively with
ice-water and methylene chloride. The thus-obtained crude product
was chromatographed on silica gel with methylene chloride and
acetonitrile. There was thus obtained
4-(tert.-butyl-dimethylsilanyloxy)-benzoic acid, elementary
analysis calculated for C.sub.13 H.sub.20 O.sub.3 Si: C=61.87%,
H=7.99%; found: C=61.71%, H=8.00%.
B. 15.60 g of
Fmoc-2,4-dimethoxy-4'-(carboxymethyloxy)-benzohydrylamine bonded to
an aminomethyl-polystyrene resin (0.55 mmol/g, Bachem AG,
Bubendorf, Switzerland; No D-1675) was stirred at room temperature
for 30 minutes with 20 ml of piperidine in 80 ml of
dimethylformamide and then filtered. The resin was washed twice
with 20 ml of dimethylformamide each time and dried in a high
vacuum for 15 minutes. The thus-obtained resin was suspended in 80
ml of dimethylformamide, 4.42 g of
4-(tert.-butyl-dimethyl-silanyloxy)-benzoic acid, 5.20 g of
2-(2-oxo-2H-pyridin-1-yl)-1,1,3,3-tetramethyl-uronium
tetrafluoroborate and 7.53 ml of ethyl-diisopropyl-amine were added
and the mixture was stirred at room temperature for 1 hour; after
filtration of the reaction mixture the resin was washed in
succession with water, isopropanol and methylene chloride and dried
at 40.degree. C. in a water-jet vacuum for 18 hours.
C. 14.50 g of resin from paragraph B. were treated in 50 ml of
tetrahydrofuran with 50 ml of tetrabutyl-ammonium fluoride solution
(1 molar in tetrahydrofuran) and stirred at room temperature for 1
hour. After filtration and washing with tetrahydrofuran, the resin
was dried at 40.degree. C. in a water-jet vacuum for 6 hours.
D. 28.40 g of the resin from paragraph C. and 47.00 g of
2,3-O-isopropylidene-1,4-di-O-(4-methyl-phenylsulfonyl)-L-threitol
were stirred at 100.degree. C. for 6 hours with the addition of
34.80 g of potassium carbonate in 100 ml of dimethylformamide.
After cooling to room temperature, the mixture was filtered and the
residue was washed in succession with water, isopropanol and
methylene chloride and dried at 40.degree. C. in a water-jet vacuum
for 18 hours.
E. 23.00 g of the resin from paragraph D. and 24.65 g of
bis-(4-hydroxy-phenyl)-methane were stirred at 100.degree. C. for 6
hours with the addition of 34.80 g of potassium carbonate in 100 ml
of dimethylformamide and worked up analogously to Example 64.D.
F. 22.00 g of the resin from paragraph E. were reacted and worked
up analogously to Example 64.D.
G. 23.40 g of the resin from paragraph F. were reacted and worked
up analogously to Example 64.E.
H. 22.85 g of the resin from paragraph G. were reacted at
140.degree. C. for 6 hours with 32.93 g of
(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate with
the addition of 33.40 g of potassium carbonate in 100 ml of
dimethylformamide and worked up analogously to Example 64.D.
I. 24.60 g of the resin from paragraph H. were stirred at room
temperature in 250 ml of 95 per cent aqueous trifluoroacetic acid
for 1 hour; thereafter the mixture was filtered and the filtrate
was concentrated. The thus-obtained residue was dissolved in 75 ml
of pyridine with 25 ml of acetic anhydride and stirred at room
temperature for 16 hours. Thereupon, the reaction mixture was
worked up extractively with ice-water and methylene chloride and
the crude product was chromatographed on silica gel with methylene
chloride and methanol. There was thus obtained
(S)-2,2',3,3'-tetra-O-acetyl-4-O-[4-[4-(2,3-bis-acetoxy-propoxy)-benzyl]-p
henyl]-4'-O-(4-carbamoyl-phenyl)-1,1'-(4,4'-methylene-diphenylene)-di-L-thr
eitol, MS: m/z 1058.8 ([M+Na].sup.+).
K 1.50 g of
(S)-2,2',3,3'-tetra-O-acetyl-4-O-[4-[4-(2,3-bis-acetoxy-propoxy)-benzyl]-p
henyl]-4'-O-(4-carbamoyl-phenyl)-1,1'-(4,4'-methylene-diphenylene)-di-L-thr
eitol in 50 ml of methanol were treated with I ml of sodium
methylate solution (5.4 molar in methanol) and stirred at room
temperature for 22 hours. The reaction mixture was adjusted to pH
4-5 with hydrochloric acid and concentrated. The thus-obtained
(R)-4'-O-(4-carbamoyl-phenyl)-4-O-[4-[4-(2,3-dihydroxy-propoxy)-benzyl]-ph
enyl]-1,1'-(4,4'-methylene-diphenylene)-di-L-threitol was dried
over phosphorus pentoxide at room temperature in a high vacuum for
4 hours and was used directly in the next step.
L. 1.00 g of
(R)-4'-O-(4-carbamoyl-phenyl)-4-O-[4-[4-(2,3-dihydroxy-propoxy)-benzyl]-ph
enyl]-1,1'-(4,4'-methylene-diphenylene)-di-L-threitol were reacted
with sulfur trioxide-trimethylamine complex in analogy to Example
1.B. There was thus obtained
(S)-4-O-[4-[4-(2,3-bis-sulfooxy-propoxy)-benzyl]-phenyl]-4'-O-(4-carbamoyl
-phenyl)-2,2',3,3'-tetra-O-sulfo-1,1'-(4,4'-methylene-diphenylene)-di-L-thr
eitol hexasodium salt, MS: m/z 1396.0 (reconstructed M).
Example A
______________________________________ Tablets:
______________________________________ 1 Compound of formula Ia or
Ib 500 mg 2 Anhydrous lactose 150 mg 3 Microcrystalline cellulose
150 mg 4 Polyvinylpyrrolidone 40 mg 5 Talc 50 mg 6 Magnesium
stearate 10 mg Tablet weight 900 mg
______________________________________
Ingredients 1-4 are sieved and mixed. This mixture is granulated
with demineralized water and the dried granulate is mixed with
ingredients 5 and 6. The mixture is pressed to tablets of suitable
form.
Example B
______________________________________ Pellets:
______________________________________ 1 Compound of formula Ia or
Ib 500 mg 2 Microcrystalline cellulose 200 mg 3 PRIMOJEL 70 mg 4
Flavour powder 10 mg 5 Talc 20 mg
______________________________________
Mixed and sieved ingredients 1-3 are moistened sufficiently with
demineralized water and pressed by means of an extruder through a
suitable perforated disc. The extrudate is transferred to a
pelleting plate, rounded-off to beadlets and subsequently dried.
The mixture is treated with sieved ingredients 4 and 5 and filled
into paper sachets (or similar).
EXAMPLE C
Injection solution
For the production of an injection solution, 50 mg of compound of
formula I as well as 0.5 mg of Tris buffer are dissolved in water
for injection ad 1 ml and the pH value is adjusted to 7.4. The
solution is filtered sterile and, after filling into ampules,
autoclaved.
* * * * *